KR20170016529A - 생물학적 활성이 감소된 신경독 - Google Patents

생물학적 활성이 감소된 신경독 Download PDF

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KR20170016529A
KR20170016529A KR1020177003042A KR20177003042A KR20170016529A KR 20170016529 A KR20170016529 A KR 20170016529A KR 1020177003042 A KR1020177003042 A KR 1020177003042A KR 20177003042 A KR20177003042 A KR 20177003042A KR 20170016529 A KR20170016529 A KR 20170016529A
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프레드 호프만
위르겐 프레베르트
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Abstract

본 발명은 약학 분야에 관한 것이다. 구체적으로, 피험자에서 생물학적 효과 기간이 감소된 신경독 폴리펩티드를 인코딩하는 폴리뉴클레오티드에 관한 것으로서, 상기 폴리펩티드는 경쇄에서 적어도 하나의 분해 신호, 또한 상기 폴리뉴클레오티드, 이렇게 인코딩된 폴리펩티드, 폴리펩티드에 특이적으로 결합한 항체를 포함한 벡터 및 숙주 세포를 포함한다. 또한, 본 발명은 상기 폴리뉴클레오티드 및 폴리펩티드를 포함한 약제, 또한 그 특이적 치료 적용에 관한 것이다. 또한, 본 발명은 폴리펩티드 및 약제의 제조 방법에 관한 것이다.

Description

생물학적 활성이 감소된 신경독 {NEUROTOXINS EXHIBITING SHORTENED BIOLOGICAL ACTIVITY}
본 발명은 약학 분야에 관한 것이다. 구체적으로, 피험자 (subject)에서 생물학적 효과 기간이 감소된 신경독 폴리펩티드를 인코딩하는 폴리뉴클레오티드에 관한 것으로서, 상기 폴리펩티드는 경쇄에서 적어도 하나의 분해 신호 (degradation signal)를 포함할뿐만 아니라, 또한 상기 폴리뉴클레오티드, 이렇게 인코딩된 폴리펩티드, 폴리펩티드에 특이적으로 결합한 항체를 포함한 벡터 및 숙주 세포를 포함한다. 또한, 본 발명은 상기 폴리뉴클레오티드 및 폴리펩티드를 포함한 약제, 또한 그 특이적 치료 적용에 관한 것이다. 또한, 본 발명은 폴리펩티드 및 약제의 제조 방법에 관한 것이다.
보툴리누스균 및 파상풍균(Clostridium botulinum and Clostridium tetani) 은 각각 매우 강력한 신경독, 즉 보툴리눔 독소(BoNT) 및 파상풍 독소 (TeNT)를 생성한다. 이들 크로스티리디아성 신경독(CNT)은 뉴런 세포에 특이적으로 결합하고 신경전달물질 방출을 파괴한다. 각각의 독소는 비활성 미처리된 약 150 kDa 단쇄 단백질로서 합성된다. 번역후 처리는 디설피드 가교의 형성 및 세균성 프로테아제에 의한 한정된 단백질 분해효소(상성)를 수반한다. 활성 신경독은 2개의 사슬, 디술피드 결합에 의해서 결합된, 대략 50 kDa의 N-말단 경쇄 및 대략 100kDa의 중쇄로 이루어진다. CNT는 3개의 영역; 즉 촉매 경쇄, 전좌영역 (N-말단 절반) 및 수용체 결합 영역(C-말단 절반)을 포함한 중쇄로 이루어진다 (Krieglstein 1990, Eur J Biochem 188, 39; Krieglstein 1991, Eur J Biochem 202, 41; Krieglstein 1994, J Protein Chem 13, 49 참조.). 보툴리눔 신경독소는 150 kDa 신경독소 단백질 및 관련 비독성 복합 단백질을 포함한 분자의 복합물로서 합성된다. 상기 복합물의 크기는 크로스티리디아성 변종 및 300 kDa 내지 900 kDa의 범위의 독특한 신경독 항원형에 기초해서 다르다. 이들 복합물 내의 복합 단백질은 신경독을 안정화시키고, 그 분해로부터 보호한다(Chen 1998, Infect Immun 66(6): 2420-2425 참조).
보툴리누스균은 보툴리눔 신경독 (BoNT)의 7개의 항원적으로 독특한 항원형 A 내지 G를 분비한다. 파상풍균에 의해 분비된 관련된 파상풍 신경독(TeNT)과 함께 모든 항원형은 SNARE 단백질을 절단함으로써 시냅스 엑소사이토시스를 차단하는 Zn2 + 엔도프로테아제이다(Couesnon, 2006, Microbiology, 152, 759 참조). CNT는 보툴리눔 중독증에서 발견된 이완성 근육 마비를 일으킨다 (Fischer 2007, PNAS 104, 10447 참조).
독성 작용에도 불구하고, 보툴리눔 독소는 많은 질병 또는 장애의 치료제로서 사용되고 있다. 보툴리눔 독소 항원형 A는 사시성, 안검경련 및 다른 장애의 치료용으로 1989년 미국에서 인간에 대한 사용이 허가되었다. 예를 들면, 상품명 BOTOX (Allergan Inc), 상품명 DYSPORT (Ipsen Ltd)으로 보툴리눔 독소 A 단백질 복합물로서 시판된다. 치료 적용에 대해서, 복합물을 근육에 직접 주입해서 치료한다. 생리적인 pH에서, 단백질 복합물로부터 독소를 방출하고 소망의 약리작용이 발생한다. 개선된, 복합물이 함유되지 않은 신경독 A 폴리펩티드 제제는 상품명 XEOMIN (Merz Pharmaceuticals GmbH)으로 시판된다. 보툴리눔 독소의 작용은 일시적이고, 이것은 치료작용을 유지하기 위해서 보툴리눔 독소의 반복적인 투여를 필요로 하는 이유이다.
크로스티리디아성 신경독은 수의근 강도를 약하게 하고, 사시증, 국소성 근긴장이상증, 예를 들면 경부 근긴장이상증 및 양성 본태성 안검경련의 치료에 효과적이다. 이들은 안면경련 경감, 및 국소경직 경감시키고, 또한 광범위한 지표, 예를 들면 위장 장애, 다한증 및 미용성 주름 개선에서 효과적인 것을 나타낸다(Jost 2007, Drugs 67, 669 을 참조한다).
그러나, 근육 강도 및 수축 약화는 질환 또는 질병, 예를 들면 상처 치유, 뼈 및 힘줄 골절 치료를 위한 부동화, 구체적으로 치핵절제, 치과 임플란트 도입 또는 관절치환술(엔도프로테시스), 관절 형성, 안과 수술에 관련된 수술후 부동화, 여드름 또는 과민성 대장 증후군에 바람직하다. 신경독은 일반적으로 상기 질병 또는 질환의 효율적인 치료에 실제로 필요로 된 기간보다 긴 시간에 걸쳐서 생물학적 효과를 나타낸다. 장기간의 근육 마비는 상기 질환 또는 질병의 치료에서 유해하거나 적어도 덜 바람직하다. 이들의 생물학적 효과를 나타내는 신경독은 아직 이용가능하지 않다.
따라서, 본 발명의 근본적인 기술적인 문제는 상기 요구에 적합한 수단 및 방법을 제공하는 것이다. 기술적인 문제는 하기 기재된 및 청구범위에서 특징으로 하는 실시형태에 의해서 해결된다.
본 발명은 약학 분야에 관한 것이다. 구체적으로, 피험자에서 생물학적 효과 기간이 감소된 신경독 폴리펩티드를 인코딩하는 폴리뉴클레오티드에 관한 것으로서, 상기 폴리펩티드는 경쇄에서 적어도 하나의 분해 신호, 또한 상기 폴리뉴클레오티드, 이렇게 인코딩된 폴리펩티드, 폴리펩티드에 특이적으로 결합한 항체를 포함한 벡터 및 숙주 세포를 포함한다. 또한, 본 발명은 상기 폴리뉴클레오티드 및 폴리펩티드를 포함한 약제, 또한 그 특이적 치료 적용에 관한 것이다. 또한, 본 발명은 폴리펩티드 및 약제의 제조 방법에 관한 것이다.
본 발명은 피험자 내에 생물학적 효과 기간이 감소된 신경독 폴리펩티드를 인코팅하는 폴리뉴클레오티드에 관한 것으로, 상기 폴리펩티드는 경쇄에서 적어도 하나의 분해 신호를 포함한다.
본원에 사용된 바와 같이 "폴리뉴클레오티드"는 하나 또는 이중 사슬 DNA 분자 또한 RNA 분자를 의미한다. 상기 용어는 게놈 DNA, cDNA, hnRNA, mRNA 또한 이러한 분자 종의 자연적으로 발생하는 또는 인공적으로 변형된 유도체를 포함한다. 폴리뉴클레오티드는 일 실시형태에서 선형 또는 환상 분자일 수 있다. 또한, 상기 신경독 폴리펩티드를 인코딩하는 핵산 서열 이외에, 본 발명의 폴리뉴클레오티드는 적당한 전사 및/또는 번역에 필요한 추가의 서열, 예를 들면 5' 또는 3'UTR 서열을 포함할 수 있다. 본 발명의 폴리뉴클레오티드는 보툴리눔 신경독의 항원적으로 다른 항원형, 즉 BoNT/A, BoNT/B, BoNT/C1, BoNT/D, BoNT/E, BoNT/F, BoNT/G 또는 파상풍 신경독(TeNT)의 하나로부터 유도 가능한 변형된 신경독 폴리펩티드를 인코딩한다. 본 발명의 형태에서, 상기 폴리뉴클레오티드는 SEQ ID NO: 1 (BoNT/A), SEQ ID NO: 3 (BoNT/B), SEQ ID NO: 5 (BoNT/C1), SEQ ID NO: 7 (BoNT/D), SEQ ID NO: 9 (BoNT/E), SEQ ID NO: 11 (BoNT/F), SEQ ID NO: 13 (BoNT/G) 또는 SEQ ID NO: 15 (TeNT)에 나타낸 핵산 서열을 포함한다. 또한, 일 형태에서 SEQ ID NO: 2 (BoNT/A), SEQ ID NO: 4 (BoNT/B), SEQ ID NO: 6 (BoNT/C1), SEQ ID NO: 8 (BoNT/D), SEQ ID NO: 10 (BoNT/E), SEQ ID NO: 12 (BoNT/F), SEQ ID NO: 14 (BoNT/G) 또는 SEQ ID NO: 16 (TeNT)의 어느 하나에 나타낸 아미노산 서열을 인코딩하는 핵산 서열을 포함한 폴리뉴클레오티드를 포함한다. 또 다른 형태에서, 상기 폴리뉴클레오티드는 하나 이상의 뉴클레오티드 치환, 결실 및/또는 추가를 포함한 상기 폴리뉴클레오티드의 변형이다. 또한, 본 발명의 변형 폴리뉴클레오티드는 SEQ ID NOs: 1, 3, 5, 7, 9, 11, 13 또는 15의 어느 하나에 나타낸 핵산 서열과 적어도 40%, 적어도 50%, 적어도 60%, 적어도 70%, 적어도 75%, 적어도 80%, 적어도 85%, 적어도 90%, 적어도 95%, 적어도 98% 또는 적어도 99% 동일한 핵산 서열 변형, 또는 SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 또는 16의 어느 하나에 나타낸 아미노산 서열과 적어도 40%, 적어도 50%, 적어도 60%, 적어도 70%, 적어도 75%, 적어도 80%, 적어도 85%, 적어도 90%, 적어도 95%, 적어도 98% 또는 적어도 99% 동일한 핵산 서열 변형을 포함한다. 본원에 사용된 "동일한"은 서열이 배열되어 가장 높은 차수 매치가 얻어지는, 2개의 핵산 서열 또는 아미노산 서열 사이에서 동일한 아미노산의 수를 결정하는 것을 특징으로 하는 서열 동일성을 의미한다. 예를 들면, BLASTP, BLASTN 또는 FASTA (Altschul 1990, J Mol Biol 215, 403)와 같은 컴퓨터 프로그램에서 코딩된 공개된 기술 또는 방법을 사용해서 산출될 수 있다. 동일성 값은 일 형태에서 전체의 아미노산 서열에 걸쳐서 산출된다. 다양한 알고리즘에 기초한 일련의 프로그램은 다른 서열과 비교하기 위해서 당업자에게 이용가능하다. 본 발명의 점에서, Needleman and Wunsch or Smith and Waterman의 알고리즘은 특히 신뢰할만한 결과를 제공한다. 서열 배열을 실시하기 위해서, GCG software packet (Genetics Computer Group 1991, 575 Science Drive, Madison, Wisconsin, USA 53711)의 일부인, 프로그램 PileUp (Higgins 1989, CABIOS 5, 151) 또는 프로그램 Gap and BestFit (Needleman 1970, J Mol Biol 48; 443; Smith 1981, Adv Appl Math 2, 482)이 사용될 수 있다. 상기 인용된 서열 동일성 값(%)은 본 발명의 또 다른 형태에서 전체의 영역에 대해서 하기와 같이 셋팅된 프로그램 GAP를 사용하여 결정되고, 달리 기재되어 있지 않으면 서열 배열의 표준 셋팅으로 사용될 것이다: Gap Weight: 50, Length Weight:　3, Average Match: 10.000 및 Average Mismatch: 0.000.
일 형태에서, 상기 변형 폴리뉴클레오티드의 각각은 하나 이상, 또 다른 형태에서 각각의 신경독 폴리펩티드의 모든 생물학적 특성, 즉 BoNT/A, BoNT/B, BoNT/C1, BoNT/D, BoNT/E, BoNT/F, BoNT/G 또는 파상풍 신경독 (TeNT)를 유지하는 폴리펩티드를 인코딩한다. 당업자에게 미처리된 전구체가 일부 생물학적 기능을 발휘하거나 또는 부분적으로 활성화될 수 있다고 생각될 수 있지만, 충분한 생물학적 활성은 단백질 분해 활성 후에 유지되는 것을 알 수 있다. 본원에 사용된 "생물학적 특성"은 (a) 수용체 결합, (b) 내면화, (c) 엔도솜 멤브레인 전체에서 시토솔(cytosol)로 이동 및/또는 (d) 시냅스의 소포 멤브레인 융합에 수반된 단백질의 세포내 단백질분해 절단을 의미한다. 생물학적 활성을 분석하기 위한 생체내 분석은 Pearce 등의 (Pearce 1994, Toxicol Appl Pharmacol 128: 69-77) 및 Dressler 등의 (Dressler 2005, Mov Disord 20:1617-1619, Keller 2006, Neuroscience 139: 629-637)에 기재된 생체외 생쥐의 편측횡격막 분석 및 생쥐의 LD50 분석을 포함한다. 생물학적 활성은 일반적으로 생쥐 유닛(MU)로 나타낸다. 본원에 사용된 바와 같이, 1MU는 복강내 주입후 특정한 생쥐의 개체수 50%를 죽이는 신경독 성분의 양, 즉 생쥐 i.p. LD50이다. 다른 형태에서, 변형 폴리뉴클레오티드는 개선된 또는 변경된 생물학적 특성을 갖는 신경독을 인코딩하고, 예를 들면 효소 인식에 대해서 개선된 절단 부위를 포함하거나 수용체 결합 또는 상기 기재된 다른 임의의 특성일 수 있다. 검출성 마커 펩티드 또는 태크를 포함한 융합 폴리펩티드를 포함한다. 형태에서, 적당한 태그는 FLAG-태크, Myc-태그 또는 His-태그이고, 이는 태그된 폴리펩티드를 효율적으로 정제한다. 일 형태에서, 검출성 마커 펩티드는 예를 들면 GFP, BFP 등과 같은 형광 단백질을 포함한다. 다른 형태에서, 변형 폴리뉴클레오티드는 다른 항원형, 예를 들면 중쇄 BONT/A 및 경쇄 BoNT/E를 포함한 융합 신경독의 적어도 2개의 신경독 폴리펩티드의 일부를 포함한 융합 신경독 폴리펩티드를 인코딩한다.
본 발명의 폴리뉴클레오티드에 의해서 인코딩된 신경독 폴리펩티드는 경쇄에서 적어도 하나의 분해 신호를 포함한다. 본 발명의 형태에서, 본 발명의 폴리뉴클레오티드에 의해서 인코딩된 신경독 폴리펩티드의 경쇄는 상기 특이한 핵산 서열 또는 그 변형의 어느 하나를 포함한 폴리뉴클레오티드에 의해서 인코딩된 경쇄로부터의 변형에 의해서 얻어진다. 신경독 폴리펩티드의 경쇄는 전구체 폴리펩티드(경쇄 폴리펩티드)의 단백질 분해적 절단에 의해서 발생한다. 경쇄는 단백질 분해적 절단의 결과로서 얻어진 전구체 폴리펩티드의 N-말단 부분이다. 상기 기재된 신경독 폴리펩티드의 경쇄의 아미노산 서열은 하기의 표에서 나타낸 절단 부위로부터 추론될 수 있다.
신경독
(세균 변종) 		Accession number 절단 부위 절단 부위(강조)를 포함한 서열
BoNT/A (Hall/62A) ABD 65472 K428/T429
K448/A449		 KLLCVRGIITSKTKSLDKGYNKALN....DLCIKV
(SEQ ID NO: 17)
BoNT/B (Okra) BAE 48264 K441/A442 IQMCKSVKAPG...................ICIDV
(SEQ ID NO: 18)
BoNT/C1 (C-6814) BAA 89713 R444/S445
K449/T450		 TKFCHKAIDGRSL....YNKTL......DCRELLV
(SEQ ID NO: 19)
BoNT/D BAA 90661 K442/N443
R445/D446		 TKVCLRLTK.........NSRD......DSTCIKV
(SEQ ID NO: 20)
BoNT/E (Beluga) CAA 43999 K419/G420
R422/K423		 IRFCKNIVSVKG......IRK........SICIEI
(SEQ ID NO: 21)
BoNT/F (NCTC10281) CAA 73972 R435/K436
K439/A440		 VKFCKSVIPRKG......TKAP......PRLCIRV
(SEQ ID NO: 22)
BoNT/G CAA 52275 IAMCKPVMYKNT......GKS........EQCIIV
(SEQ ID NO: 23)
TeNT P 04958 R449 (R455) IGLCKKIIPPTNIRENLYNRTASLTDLGGELCIKI
(SEQ ID NO: 24)
본원에 사용된 "분해 신호"는 신경독이 적용된 유기체에서 존재한 내생적인 분해 경로에 의해서 신경독 폴리펩티드의 분해를 증가시킨 신경독 폴리펩티드의 경쇄의 변형을 의미한다. 일 형태에서, 분해 경로는 프로테아솜 분해 경로 또는 리소솜 분해 경로일 것이다. 또 다른 형태에서, 분해 경로는 예를 들면 하나 이상의 단백질 분해적 절단 단계에 의해서 신경독 폴리펩티드의 부분적인 분해를 일으킬 수 있다. 상기 분해 신호는 경쇄에 도입되고(즉, 경쇄 내에서 (내부에) 위치되고), 또는 N- 또는 C-말단에 연결될 수 있다. 당업자는 적당한 분해 신호, 및 이들을 신경독 폴리펩티드의 경쇄에 도입하거나 연결하는 방법을 알 수 있다. 또한, 당업자는 재조합 분자의 생물학적 방법 또는 화학적 변형을 적용함으로써 이러한 신경독 폴리펩티드를 적어도 하나의 분해 신호로 인코딩한 폴리뉴클레오티드를 발생시킬 수 있다. 예를 들면, 부위 특이적인 돌연변이는 하기에 관한 분해 신호를 도입하기 위해서 사용할 수 있다. 또한, 신경독 폴리펩티드 및 상정된 분해 신호의 코딩 서열을 포함한 폴리뉴클레오티드의 핵산 서열이 설계되고, 전체의 폴리뉴클레오티드는 화학적으로 합성될 수 있다.
일 형태에서, 상기 분해 신호는 하기의 군으로부터 선택된다:
a) 적어도 하나의 내부에 또는 말단에 도입된 PEST 모티프 (motifs),
b) 적어도 하나의 내부에 또는 말단에 도입된 E3 리가아제 인식 모티프
c) N-말단 올리고-리신 잔기,
d) N-말단에 결합된 결합 유비퀴틴
e) N-말단 프롤린을 염기성 아미노산으로 치환
f) 표면-존재한 아미노산 잔기를 리신으로 치환,
g) 표면-존재한 아미노산 잔기를 리신으로 치환하는 것과 함께 N-말단 프롤린을 염기성 아미노산으로 치환
일 형태에서, E3 리가아제 인식 모티프는 하기의 표에서 나타낸 바와 같은 공통 서열을 갖는다(여기서, "X"는 천연 발생 아미노산의 어느 하나를 나타낼 수 있다)
E3 유비퀴틴 리가아제 인식 모티프 (consensus)
VBCCul2 ALAPYIP (SEQ ID NO: 25)
MNM2 RFMDYWEGL (SEQ ID NO: 26)
FXXXLWXXL (SEQ ID NO: 27)
Smurf2 ELESPPPPYSRYPM (SEQ ID NO: 28)
RN181 KVGFFKR (SEQ ID No: 29)
E3alpha LLVRGRTLVV (SEQ ID NO 30
SCF DRHDSGLDSM (SEQ ID NO: 31)
Siah PXAXVXP (SEQ ID NO: 32)
Itch PPXYXXM (SEQ ID NO: 33)
Nedd4-2 PPXY (SEQ ID No: 34)
분해 신호로서 PEST 모티프가 공지되어 있다(Rogers 1986, Science 234: 364-368, Rechsteiner 1996, TIBS 21: 267-271, Belizario 2008, Science 9: 210-220). 일 형태에서, PEST 모티프는 이러한 단백질, GCN4, IκBα, Fos, Ornithine decarboxylase, Cactus, CLN2, CLN 3 또는 NIMA의 어느 하나에 대해서 Rechsteiner 1996, TIBS 21: 267-271, 표 1 (여기에 참조로서 혼입됨)에 개시된 서열을 갖는다.
본 발명의 폴리뉴클레오티드에 의해서 인코딩된 변형된 신경독 폴리펩티드는 변형되지 않은 신경독 폴리펩티드에 비해서 투여시에 피험자 내에 생물학적 효과의 기간을 감소시킬 것이다. 일 형태에서, 피험자에서 관찰된 상기 생물학적 효과는 근육 마비, 즉 (가역성) 근육의 수축능력의 불활성화를 일으킨다. 일 형태에서, 상기 작용은 소위 생쥐의 흐름 분석(running assay)(Keller 2006, Neuroscience 139: 629-637)에 의해서 시험될 수 있다. 생물학적 효과는 당업자에 의해서 더 이상 지체 없이 결정될 수 있다. 일 형태에서, 생물학적 효과 감소 기간은 통계적으로 상당히 감소된 기간을 의미한다. 작용의 기간이 통계적으로 상당히 감소된 경우, 표준 통계 시험을 적용함으로써 당업자에 의해서 결정될 수 있고, 예를 들면 신뢰도 간격, p-값 결정, 스튜던트 t-시험, MannWhitney 시험 등의 결정을 들 수 있다. 바람직한 신뢰도 간격은 적어도 90%, 적어도 95%, 적어도 97%, 적어도 98% 또는 적어도 99 %이다. p값은 바람직하게 0.1, 0.05, 0.01, 0.005, 또는 0.0001이다. 바람직하게, 본 발명에 의해서 예상된 가능성은 진단이 소정의 무리 또는 개체의 피험자의 적어도 60%, 적어도 70%, 적어도 80%, 또는 적어도 90% 에 대해서 정확할 것이다. 일 형태에서, 상기 감소된 기간은 정상 기간의 75% 미만, 70% 미만, 65% 미만, 60% 미만, 55% 미만, 50% 미만, 45% 미만, 40% 미만, 30% 미만 또는 20% 미만, 즉 미변형된 신경독 폴리펩티드에 대해서 관찰된 기간을 지속한다. 일 형태에서, 일반적인 기간은 BoNT/A의 경우에 대략 4개월, BoNT/B의 경우에 2 개월, BoNT/C의 경우에 대략 3내지 4개월, 또는 BoNT/E의 경우에 대략 4주 지속한다. (Foran, J Biol. Chem. 278(2): 1363-1371, Eleopra 1998, Neurosci Lett. 13, 256(3): 135-138, Eleopra 1997, Neurosci Lett. 14,224(2): 91-94, Sloop 1997, Neurology 49(1): 189-194, Washbourne 1998, J Physiol Paris 92(2): 135-139). 작용의 기간은 피험자 내에 개개의 영향, 예를 들면 유전적인 배경, 나이, 라이프스타일, 등에 의존한 것을 이해한다. 따라서, 본원에 의미하는 대략 기간은 25% 이하, 20% 이하, 15% 이하, 10 % 이하 또는 5% 이하의 표준 편차와 함께, 각각의 신경독 폴리펩티드에 대해서 상기 나타낸 바와 같은 기간을 의미한다.
바람직하게, 본 발명에 따라서 신경독 폴리펩티드는 투여시 피험자내에 생물학적 효과가 감소되도록 변형될 수 있는 것을 알 수 있다. 주로, 이는 경쇄의 지속이 생물학적 효과 기간과 관련된 것을 알 수 있기 때문에, 상기 신경독 폴리펩티드의 경쇄에 분해 신호를 도입하거나 결합함으로써 달성될 수 있다. 신경독 폴리펩티드에 의해서 도출된 생물학적 효과의 감소된 기간은 상처 치유를 용이하게 하기 위해서 신경 작용의 불활성, 예를 들면 근육 마비를 필요로 하는 다양한 의학적 적용에 유익하다.
본 발명은 본 발명의 폴리뉴클레오티드를 포함한 벡터에 관한 것이다.
"벡터"는 바람직하게 파지, 플라스미드, 바이러스 또는 레트로바이러스 벡터, 또한 인공적 크로모솜, 예를 들면 세균 또는 이스트 인공적 크로모솜을 포함한다. 또한, 상기 용어는 목적 구성을 게놈 DNA에 랜덤 또는 부위 특이적으로 통합시키는 목적 구성에 관한 것이다. 이러한 목적 구성은 바람직하게 하기 기재된 바와 같이 동종 또는 이종 재조합의 충분한 길이의 DNA를 포함한다. 일 형태에서 본 발명의 폴리뉴클레오티드를 포함한 벡터는 숙주에서 증식 및/또는 선택에 대한 선택성 마커를 포함한다. 벡터는 공지된 다양한 방법에 의해서 숙주 세포에 포함될 수 있다. 예를 들면, 플라스미드 벡터는 칼슘 포스페이트 석출물 또는 루비듐 클로라이드 석출물과 같은 석출물, 또는 충전된 리피드와 복합물 또는 탄소계 클러스터, 예를 들면 플러렌에서 도입될 수 있다. 또한, 플라스미드 벡터는 가열 충격 또는 전기천공법에 의해서 도입될 수 있다. 벡터가 바이러스이면, 숙주 세포에 적용하기 전에 적당한 패키징 세포 라인을 사용해서 실험관에서 패키징될 수 있다. 레트로바이러스는 복제 가능하거나 복제 결함일 수 있다. 후자의 경우에, 바이러스 증식은 일반적으로 상보적인 숙주/세포에서 발생할 수 있다. 또한, 본 발명의 형태에서, 폴리뉴클레오티드는 상기 벡터에서 진핵 또는 원핵 숙주 세포 또는 그 독립된 분획에서 발현하는 발현 제어 서열에 조작적으로 결합된다. 폴리뉴클레오티드의 발현은 폴리뉴클레오티드를 번역 가능한 mRNA로의 전사를 포함한다. 숙주 세포에서 발현을 보장하는 조절 요소가 공지되어 있다. 일 형태에서, 이들은 전사의 개시를 보장하는 조절 배열 및/또는 전사의 종결 및 전사 산물의 안정화를 보장하는 폴리-A 신호를 포함한다. 추가의 조절 요소는 잔사 또한 번역 인핸서를 포함할 수 있다. 원핵생물 숙주 세포에서 발현 가능한 조절 요소는, 예를 들면 E.coli에서 lac-, trp- 또는 tac- 촉진제를 포함하고, 진핵생물 숙주 세포에서 발현을 허가하는 조절 요소는 이스트에서 AOXl- 또는 GAL1 촉진제이고 또는 CMV-, SV40, RSV- 프로모터(Rous sarcoma virus), CMV-인핸서, SV40-인핸서 또는 포유류 또는 다른 동물 세포에서 글로빈 인트론이다. 또한, 유도되는 발현 대조 서열은 본 발명에 의해서 포함된 발현 벡터에 사용될 수 있다. 이러한 유도 가능한 벡터는 tet 또는 lac 조작자 서열, 또는 열 충격 또는 다른 환경 요소에 의해서 유도 가능한 서열을 포함할 수 있다. 적당한 발현 대조 서열이 공지되어 있다. 전사의 개시에 기인한 요소 이외에, 이러한 조절 요소는 전사 말단 신호, 예를 들면 SV40-poly-A 부위 또는 tk-poly-A 부위, 폴리펩티드 하부 흐름을 포함할 수 있다. 본 발명에서, 적당한 발현 벡터는 예를 들면 Okayama-Berg cDNA 발현 벡터 pcDV1 (Pharmacia), pBluescript (Stratagene), pCDM8, pRc/CMV, pcDNA1, pcDNA3 (Invitrogen) 또는 pSPORT1가 알려져 있다. 바람직하게, 상기 벡터는 발현 벡터 및 유전자 전달 또는 목적의 벡터이다. 발현 벡터는 바이러스, 예를 들면 레트로바이러스, 백신 바이러스, 아데노 관련 바이러스, 헤르페스 바이러스 또는 소 유두종 바이러스로부터 유래된 발현 벡터는 본 발명의 벡터 또는 폴리뉴클레오티드를 목적의 세포 개체로의 전달에서 사용될 수 있다. 당업자에게 공지된 방법은 재조합 바이러스 벡터를 구성하기 위해서 사용될 수 있다; 예를 들면, Sambrook, Molecular Cloning A Laboratory Manual, Cold Spring Harbor Laboratory (1989) N.Y. and Ausubel, Current Protocols in Molecular Biology, Green Publishing Associates and Wiley Interscience, N.Y. (1994)에 기재된 방법을 참조한다.
또한, 본 발명은 본 발명의 폴리뉴클레오티드 또는 벡터를 포함한 숙주 세포에 관한 것이다.
본원에 사용된 "숙주 세포"는 진핵세포 및 원핵 숙주 세포를 포함한다. 일 형태에서 숙주 세포는 세균성 세포이고, 또 다른 형태에서 피르미쿠트 세균 세포이다. 일 형태에서, 상기 세균성 숙주 세포는 대장균 숙주 세포이다. 또 다른 형태에서, 클로스트리디움 숙주 세포이다. 또 다른 형태에서, 상기 클로스트리디움 숙주 세포는 보툴리눔균 숙주 세포이고, 또 다른 형태에서 보툴리눔균의 7개의 다른 항원형 중 하나의 세포이다. 또 다른 형태에서, 세균성 숙주 세포는 파상풍균 숙주 세포이다. 또 다른 형태에서, 숙주 세포는 바실러스 숙주 세포이고, 특히 바실러스 마그테리움 숙주 세포이다. 진핵 숙주 세포는 이스트 숙주 세포와 같은 균류 숙주 세포 또는 독성 단백질의 제조에 적합한 동물 세포주의 세포이다.
본 발명은 본 발명의 플리뉴클레오티드에 의해서 인코딩된 폴리펩티드를 포함한다.
본원에 사용된 "폴리펩티드"는 숙주 세포의 복합 단백질 (HA70, HA17, HA33, 또는 NTNH (NBP))을 포함하는, 다른 폴리펩티드가 필수적으로 없는, 분리되거나 본질적으로 정제된 폴리펩티드 또는 부가적으로 다른 단백질을 포함한 폴리펩티드 제제 (polypeptide preparations)를 포함한다. 또한, 용어는 화학적으로 변경된 폴리펩티드를 포괄한다. 이러한 변형은 인공적인 변형 또는 자연적으로 발생한 변형일 수 있다. 상기 기재된 바와 같이, 본 발명의 폴리펩티드는 상기 기재된 신경독 폴리펩티드의 생물학적 특성을 가질 수 있다. 또한, 투여시에 피험자에서 생물학적 효과의 기간이 감소시킬 수 있다. 일 형태에서, 본 발명의 폴리펩티드는 보다 상세하게 본원에 기재된 바와 같이 폴리펩티드의 제조방법에 의해서 제조될 수 있다. 본 발명의 형태에서, 폴리펩티드 제제는 신경독 폴리펩티드의 복합물 및 그 복합 단백질을 포함한 것이 예상된다.
또한, 본 발명은 본 발명의 폴리펩티드에 특이적으로 결합한 항체에 관한 것이다.
본 발명의 폴리펩티드에 대한 항체는 항원으로서 본 발명에 따른 정제된 폴리펩티드 또는 유도된 적합한 단편을 사용해서 공지된 방법에 의해서 제조될 수 있다. 항원으로서 적합한 단편은 공지된 항원성-결정 알고리즘에 의해서 식별될 수 있다. 이러한 단편은 단백질 분해에 의해서 본 발명의 폴리펩티드로부터 얻어지거나 또는 합성 펩티드일 수 있다. 일 형태에서, 본 발명의 항체는 모노클로날 항체, 폴리클로날 항체, 단쇄 항체, 인간 또는 인간화 항체 또는 성숙화, 또는 키메라 항체 또는 그 단편이다. 본 발명에 의한 항체로서 이중특이성, 합성 항체, 항체 단편, 예를 들면 Fab, Fv 또는 scFv 단편, 등 또는 이들 단편의 화학적으로 변형 유도체를 포함한다. 본 발명의 항체는 본 발명의 폴리펩티드에 특이적으로 결합할 것이다(즉, 다른 폴리펩티드 또는 펩티드와 교차반응하지 않는다). 특이적으로, 항체는 미변형된 신경독 폴리펩티드와 교차 반응하지 않을 수 있다. 특이적 결합은 다양한 공지의 방법에 의해서 시험될 수 있다. 항체 또는 그 단편은 예를 들면 Harlow and Lane "Antibodies, A Laboratory Manual", CSH Press, Cold Spring Harbor, 1988에 기재된 방법을 사용해서 제조할 수 있다. 모노클로날 항체는 Kohler 등의 (Kohler 1975, Nature 256 (1975), 495) or Galfre(Galfre 1981, Meth. Enzymol. 73 (1981))에 기재된 방법을 사용하여 제조될 수 있다. 이는 항원, 즉 본 발명의 폴리펩티드 또는 그 면역성 항원 단편에 의해서 면역력을 갖는 포유류로부터 유도된 비장세포에 대한 생쥐의 골수종 세포의 융합을 포함한다. 항체는 본 발명의 폴리펩티드의 면역침강 및 면역학적 국재 결정, 또한 재조합 유기체에서 상기 폴리펩티드의 존재를 모니터링 및 본 발명에 따른 단백질과 상호작용하는 화합물을 식별화하는 데에 사용될 수 있다. 예를 들면, BIAcore 시스템에서 사용된 표면 플라즈몬 공명이 사용되어 본 발명의 단백질의 에피토프에 결합한 파지 항체의 효율을 증가시킬 수 있다(Schier 1996, Human Antibodies Hybridomas 7, 97-105; Malmborg 1995, J. Immunol. Methods 183, 7-13).
본 발명의 폴리뉴클레오티드 또는 폴리펩티드는 일반적으로 약제로서 사용될 수 있다.
본원에 사용된 "약제"는 일 형태에서 생물학적으로 활성 신경독 폴리펩티드를 함유한 약학적 조성물 또는 약학적 활성 화합물로서 이를 인코딩한 폴리뉴클레오티드를 의미한다. 상기 약제는 다양한 질병 또는 장애가 있는 인간 또는 동물 치료하기 위해서 치료적으로 유효한 양으로 사용될 수 있다. 약물은 소망의 적용 목적에 의존한 다양한 방법에 의해서 제형화될 수 있다. 본 발명에 따른 약제의 다른 형태가 하기에 기재된다.
일 형태에서, 약제는 약학적 조성물로서 하나 이상의 약학적으로 허용가능한 담체 (carriers)에서 본 발명의 생물학적 활성 신경독 폴리펩티드를 포함한다. 약학적 허용가능한 담체는 제형의 다른 성분과 상용가능하고 그 수용체에 유해하지 않는 점에서 허용되어야 한다. 사용된 약학적 담체는 고체, 겔 또는 액체을 포함할 수 있다. 고체 담체로는 락토오스, 테라 알바, 슈크로오스, 탈크, 겔라틴, 아가, 펙틴, 아카시아, 마그네슘 스테아레이트, 스테아르산, 등이다. 액체 담체로는 글리세롤, 인산 완충염 용액, 물, 에멀젼, 다양한 형태의 습윤제이다. 적당한 담체로는 상기 기재된 것 및 공지된 그외의 것을 포함하고, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania을 참조한다. 담체는 약제의 활성 성분이 본 발명의 폴리뉴클레이오티드이면 유전자 치료에 적당한 바이러스 또는 레트로바이러스일 수 있는 것으로 이해될 것이다.
일 형태에서, 약제는 투여 전에 희석액에 용해될 것이다. 희석액은 조합의 생물학적 활성에 영향을 미치지 않도록 선택된다. 이러한 희석액으로는 증류수 또는 생리적 식염수이다. 또한, 약학적 조성물 또는 제형은 다른 담체 또는 비독성, 비-치료의, 비-면역의 안정제 등을 포함할 수 있다. 따라서, 일 형태에서 본 발명의 비독성 폴리펩티드는 액체 또는 동결건조된 형태로 존재할 수 있다. 일 형태에서, 글리세롤, 단백질 안정화제(HSA) 또는 비-독성 안정화제, 예를 들면 폴리비닐피롤리돈(PVP), 히알루론산 또는 자유 아미노산과 함께 존재할 수 있다. 일 형태에서, 적당한 비-단백질 안정화제는 WO 2005/007185 또는 WO 2006/020208에 기재된다.
다른 형태에서, 약제는 신경독 폴리펩티드를 포함한 용액으로서 제공될 것이다. 또한, 용액은 상기 기재된 담체 또는 안정화제를 포함할 수 있다. 신경독 폴리펩티드의 안정한 액체 제형은 US 7,211, 261에 기재된 바와 같이 제공될 수 있다.
일 형태에서, 약학적 조성물은 경피 투여된다. 종래에 약제는 소망의 의학적 적응에 따라서 근육 내 또는 피하(샘 근방)에 투여될 수 있다. 그러나, 화합물의 상태 및 작용모드에 따라서, 약학적 조성물은 다른 경로에 의해서 투여될 수 있다.
치료적 유효량은 본 명세서에 관한 질환 또는 질병을 수반한 증상을 방지하거나, 개선하거나 치료한 본 발명의 신경독 폴리펩티드 또는 폴리뉴클레오티드의 양을 의미한다. 화합물의 치료적 효능 및 독성은 세포 배양물 또는 실험적 동물, 예를 들면 ED50(개체의 50%에서 치료적으로 유효한 양) 및 LD50(개체의 50%에 치명적인 양)에서 표준 약학적 절차에 의해서 결정될 수 있다. 치료적 및 독성 작용 사이의 투여율이 치료 지수이며, LD50/ED50로 표현될 수 있다. 본 발명의 약물은 개개의 환자에 따라서 투여 조절량을 예상하기 위해서, 처방자 또는 사용자 지시사항 내에 투여량 추천사항을 포함할 것이다.
본원에 관한 약물은 본 명세서에서 인용된 질병 또는 질환을 치료하거나 개선하거나 방지하기 위해서 적어도 1회 투여되는 것으로 개발된다. 그러나, 상기 약제는 1회 초과해서 투여될 수 있다.
또 다른 형태에서 본 발명에 따른 약제는 그 제형중에서 약학적 조성물에 첨가된 생물학적으로 활성 신경독 폴리펩티드 이외에 약물을 포함할 수 있다.
또한, 본 발명은 상처 치유, 뼈 및 힘줄 골절 치료를 위한 부동화, 구체적으로 치핵절제, 치과 임플란트 도입 또는 관절치환술(엔도프로테시스), 관절 형성, 안과 수술에 관련된 수술 후 부동화, 여드름 또는 과민성 대장 증후군의 약제를 제조하기 위해서 본 발명의 폴리뉴클레오티드 또는 폴리펩티드를 사용하는 것에 관한 것이다.
상기 질환 또는 질병에 관한 증상은 당업자에게 공지되어 있고 약물의 표준 텍스트북, 예를 들면 Stedman 또는 Pschyrembl에 기재된다.
또한, 본 발명은 피험자가 신경독 치료에 민감한지를 결정하기 위한 진단 약제를 제조하기 위해서 본 발명의 폴리뉴클레오티드 또는 폴리펩티드를 사용하는 것에 관한 것이다.
상기의 진단 약제는 상기에 기재된 신경독 폴리펩티드 약제이다. 그러나, 약제는 피험자가 적당한 투여 요법의 모두 또는 그 결정에서 신경독 폴리펩티드에 대응하는 지를 결정하는 투여요법에서 잠시 동안 적용된다. 상기 신경독 폴리펩티드는 치료 포텐셜을 갖지만, 일 형태에서 치료 또는 개선보다 차라리 진단 목적에 요긴하게 사용되기 때문에, 약제를 "진단 약제"라고 한다. 따라서, 본 발명의 변형된 신경독 폴리펩티드를 갖는 시간-제한 프리-스크린은 비-변형된 신경독을 사용한 치료에 민감한 피험자의 선택 또한 적당한 투여의 결정을 도울 수 있다. 더 긴 시간에 걸쳐서 일반적으로 지속된 비-변형된 신경독에 기초한 치료의 잠재적 부작용은 본 발명의 변형된 신경독 폴리펩티드에 의해서 유도된 생물학적 효과의 기간의 감소 때문에 감소될 수 있다.
본 발명은 하기의 단계를 포함한 본 발명의 폴리뉴클레오티드에 의해서 인코딩된 신경독 폴리펩티드의 제조에 대한 방법을 포함한다:
a) 본 발명의 폴리뉴클레오티드에 의해서 인코딩된 신경독 폴리펩티드를 발현하는 조건하에서 본 발명의 숙주 세포를 배양하는 단계, 및
b) a)의 숙주 세포 배양액으로부터 본 발명의 폴리뉴클레오티드에 의해서 인코딩된 신경독 폴리펩티드를 얻는 단계.
일 형태에서, 폴리펩티드는 친화성 크로마토그래피, 크기 배제 크로마토그래피, 고압 액체 크로마토그래피(HPLC)를 포함한 모든 종래의 정제 방법 및 항체 석출을 포함한 석출 방법에 의해서 배양물로부터 얻어질 수 있다. 또한, 일 형태에서, 본 발명의 방법에 의해서 얻어진 신경독 폴리펩티드는 복합 단백질을 함유하지 않을 수 있다. 또 다른 형태에서, 신경독 폴리펩티드는 신경독 폴리펩티드 복합 단백질을 포함한 복합물로서 얻어질 수 있다. 또한, 본원에 사용된 바와 같이, 얻어진 것은 신경독 폴리펩티드의 활성을 포함한다. 이것은 내생 또는 외인성(예를 들면 재조합 발현) 프로테아제에 의한 세포간 또는 예를 들면 상기 정제 전, 중 또는 후에 신경독 폴리펩티드를 절단시키는 조건하에서 프로테아제와 접촉에 의한 세포의 외측에 (단쇄) 신경독 폴리펩티드 전구체의 단백질 분해적 절단에 의해서 달성될 수 있다.
또한, 약제의 제조방법은 본 발명에 따르는 것으로서, 본 발명의 상기 방법의 단계 및 약제로서 본 발명의 폴리펩티드에 의해서 인코딩된 신경독 폴리펩티드를 제형하는 추가의 단계를 포함한다.
이러한 약제 제조의 방법은 품질, 약학적 안전성 및 약제 효능을 보장하기 위해서 약제의 GMP 표준에 따라서 실시된다. 약제의 적당한 제형은 이러한 명세서에 기재된다. 당업자는 이러한 제형의 제조방법을 알 수 있다.
본 발명은 본 발명의 방법의 단계 및 화장품 조성물로서 신경독 폴리펩티드를 제형하는 추가의 단계를 포함한 화장품 조성물의 제조방법을 포함한다.
본원에 사용된 "화장품 조성물"은 상기 약학적 조성물에 기재된 바와 같이 제형될 수 있다. 마찬가지로 화장품 조성물에 대해서, 본 발명의 화합물은 실질적으로 순수한 형태로 사용되는 것이 예상된다. 그러나, 불순물은 약제에 대해서 덜 중요할 수 있다. 다른 형태에서, 화장품 조성물은 근육 내에 적용될 수 있다. 본 발명의 또 다른 형태에서, 신경독을 포함한 화장품 조성물은 항주름제로서 제형화될 수 있다.
본 발명은 이러한 화장품 조성물 및 항주름제로서 사용될 화장품 조성물을 제조하기 위한 본 발명의 폴리펩티드 또는 폴리뉴클레오티드의 사용에 관한 것이다.
본 명세서의 모든 참조문헌은 전체 개시 내용 및 본 명세서에 특이적으로 언급된 개시 내용에 의해서 포함된다.
<110> Merz Pharma GmbH & Co.KGaA <120> Neurotoxins exhibiting shortened biological activity <130> MP66380EP <160> 34 <170> PatentIn version 3.5 <210> 1 <211> 3891 <212> DNA <213> Clostridium botulinum <400> 1 atgccatttg ttaataaaca atttaattat aaagatcctg taaatggtgt tgatattgct 60 tatataaaaa ttccaaatgc aggacaaatg caaccagtaa aagcttttaa aattcataat 120 aaaatatggg ttattccaga aagagataca tttacaaatc ctgaagaagg agatttaaat 180 ccaccaccag aagcaaaaca agttccagtt tcatattatg attcaacata tttaagtaca 240 gataatgaaa aagataatta tttaaaggga gttacaaaat tatttgagag aatttattca 300 actgatcttg gaagaatgtt gttaacatca atagtaaggg gaataccatt ttggggtgga 360 agtacaatag atacagaatt aaaagttatt gatactaatt gtattaatgt gatacaacca 420 gatggtagtt atagatcaga agaacttaat ctagtaataa taggaccctc agctgatatt 480 atacagtttg aatgtaaaag ctttggacat gaagttttga atcttacgcg aaatggttat 540 ggctctactc aatacattag atttagccca gattttacat ttggttttga ggagtcactt 600 gaagttgata caaatcctct tttaggtgca ggcaaatttg ctacagatcc agcagtaaca 660 ttagcacatg aacttataca tgctggacat agattatatg gaatagcaat taatccaaat 720 agggttttta aagtaaatac taatgcctat tatgaaatga gtgggttaga agtaagcttt 780 gaggaactta gaacatttgg gggacatgat gcaaagttta tagatagttt acaggaaaac 840 gaatttcgtc tatattatta taataagttt aaagatatag caagtacact taataaagct 900 aaatcaatag taggtactac tgcttcatta cagtatatga aaaatgtttt taaagagaaa 960 tatctcctat ctgaagatac atctggaaaa ttttcggtag ataaattaaa atttgataag 1020 ttatacaaaa tgttaacaga gatttacaca gaggataatt ttgttaagtt ttttaaagta 1080 cttaacagaa aaacatattt gaattttgat aaagccgtat ttaagataaa tatagtacct 1140 aaggtaaatt acacaatata tgatggattt aatttaagaa atacaaattt agcagcaaac 1200 tttaatggtc aaaatacaga aattaataat atgaatttta ctaaactaaa aaattttact 1260 ggattgtttg aattttataa gttgctatgt gtaagaggga taataacttc taaaactaaa 1320 tcattagata aaggatacaa taaggcatta aatgatttat gtatcaaagt taataattgg 1380 gacttgtttt ttagtccttc agaagataat tttactaatg atctaaataa aggagaagaa 1440 attacatctg atactaatat agaagcagca gaagaaaata ttagtttaga tttaatacaa 1500 caatattatt taacctttaa ttttgataat gaacctgaaa atatttcaat agaaaatctt 1560 tcaagtgaca ttataggcca attagaactt atgcctaata tagaaagatt tcctaatgga 1620 aaaaagtatg agttagataa atatactatg ttccattatc ttcgtgctca agaatttgaa 1680 catggtaaat ctaggattgc tttaacaaat tctgttaacg aagcattatt aaatcctagt 1740 cgtgtttata catttttttc ttcagactat gtaaagaaag ttaataaagc tacggaggca 1800 gctatgtttt taggctgggt agaacaatta gtatatgatt ttaccgatga aactagcgaa 1860 gtaagtacta cggataaaat tgcggatata actataatta ttccatatat aggacctgct 1920 ttaaatatag gtaatatgtt atataaagat gattttgtag gtgctttaat attttcagga 1980 gctgttattc tgttagaatt tataccagag attgcaatac ctgtattagg tacttttgca 2040 cttgtatcat atattgcgaa taaggttcta accgttcaaa caatagataa tgctttaagt 2100 aaaagaaatg aaaaatggga tgaggtctat aaatatatag taacaaattg gttagcaaag 2160 gttaatacac agattgatct aataagaaaa aaaatgaaag aagctttaga aaatcaagca 2220 gaagcaacaa aggctataat aaactatcag tataatcaat atactgagga agagaaaaat 2280 aatattaatt ttaatattga tgatttaagt tcgaaactta atgagtctat aaataaagct 2340 atgattaata taaataaatt tttgaatcaa tgctctgttt catatttaat gaattctatg 2400 atcccttatg gtgttaaacg gttagaagat tttgatgcta gtcttaaaga tgcattatta 2460 aagtatatat atgataatag aggaacttta attggtcaag tagatagatt aaaagataaa 2520 gttaataata cacttagtac agatatacct tttcagcttt ccaaatacgt agataatcaa 2580 agattattat ctacatttac tgaatatatt aagaatatta ttaatacttc tatattgaat 2640 ttaagatatg aaagtaatca tttaatagac ttatctaggt atgcatcaaa aataaatatt 2700 ggtagtaaag taaattttga tccaatagat aaaaatcaaa ttcaattatt taatttagaa 2760 agtagtaaaa ttgaggtaat tttaaaaaat gctattgtat ataatagtat gtatgaaaat 2820 tttagtacta gcttttggat aagaattcct aagtatttta acagtataag tctaaataat 2880 gaatatacaa taataaattg tatggaaaat aattcaggat ggaaagtatc acttaattat 2940 ggtgaaataa tctggacttt acaggatact caggaaataa aacaaagagt agtttttaaa 3000 tacagtcaaa tgattaatat atcagattat ataaacagat ggatttttgt aactatcact 3060 aataatagat taaataactc taaaatttat ataaatggaa gattaataga tcaaaaacca 3120 atttcaaatt taggtaatat tcatgctagt aataatataa tgtttaaatt agatggttgt 3180 agagatacac atagatatat ttggataaaa tattttaatc tttttgataa ggaattaaat 3240 gaaaaagaaa tcaaagattt atatgataat caatcaaatt caggtatttt aaaagacttt 3300 tggggtgatt atttacaata tgataaacca tactatatgt taaatttata tgatccaaat 3360 aaatatgtcg atgtaaataa tgtaggtatt agaggttata tgtatcttaa agggcctaga 3420 ggtagcgtaa tgactacaaa catttattta aattcaagtt tgtatagggg gacaaaattt 3480 attataaaaa aatatgcttc tggaaataaa gataatattg ttagaaataa tgatcgtgta 3540 tatattaatg tagtagttaa aaataaagaa tataggttag ctactaatgc atcacaggca 3600 ggcgtagaaa aaatactaag tgcattagaa atacctgatg taggaaatct aagtcaagta 3660 gtagtaatga agtcaaaaaa tgatcaagga ataacaaata aatgcaaaat gaatttacaa 3720 gataataatg ggaatgatat aggctttata ggatttcatc agtttaataa tatagctaaa 3780 ctagtagcaa gtaattggta taatagacaa atagaaagat ctagtaggac tttgggttgc 3840 tcatgggaat ttattcctgt agatgatgga tggggagaaa ggccactgta a 3891 <210> 2 <211> 3661 <212> PRT <213> Clostridium botulinum <400> 2 Met Glu Thr Pro Arg Pro His Glu Val Ala Leu Ala Ser Asn Leu Tyr 1 5 10 15 Ser Gly Leu Asn Pro His Glu Ala Ser Asn Thr Tyr Arg Leu Tyr Ser 20 25 30 Ala Ser Pro Pro Arg Val Ala Leu Ala Ser Asn Gly Leu Tyr Val Ala 35 40 45 Leu Ala Ser Pro Ile Leu Glu Ala Leu Ala Thr Tyr Arg Ile Leu Glu 50 55 60 Leu Tyr Ser Ile Leu Glu Pro Arg Ala Ser Asn Ala Leu Ala Gly Leu 65 70 75 80 Tyr Gly Leu Asn Met Glu Thr Gly Leu Asn Pro Arg Val Ala Leu Leu 85 90 95 Tyr Ser Ala Leu Ala Pro His Glu Leu Tyr Ser Ile Leu Glu His Ile 100 105 110 Ser Ala Ser Asn Leu Tyr Ser Ile Leu Glu Thr Arg Pro Val Ala Leu 115 120 125 Ile Leu Glu Pro Arg Gly Leu Ala Arg Gly Ala Ser Pro Thr His Arg 130 135 140 Pro His Glu Thr His Arg Ala Ser Asn Pro Arg Gly Leu Gly Leu Gly 145 150 155 160 Leu Tyr Ala Ser Pro Leu Glu Ala Ser Asn Pro Arg Pro Arg Pro Arg 165 170 175 Gly Leu Ala Leu Ala Leu Tyr Ser Gly Leu Asn Val Ala Leu Pro Arg 180 185 190 Val Ala Leu Ser Glu Arg Thr Tyr Arg Thr Tyr Arg Ala Ser Pro Ser 195 200 205 Glu Arg Thr His Arg Thr Tyr Arg Leu Glu Ser Glu Arg Thr His Arg 210 215 220 Ala Ser Pro Ala Ser Asn Gly Leu Leu Tyr Ser Ala Ser Pro Ala Ser 225 230 235 240 Asn Thr Tyr Arg Leu Glu Leu Tyr Ser Gly Leu Tyr Val Ala Leu Thr 245 250 255 His Arg Leu Tyr Ser Leu Glu Pro His Glu Gly Leu Ala Arg Gly Ile 260 265 270 Leu Glu Thr Tyr Arg Ser Glu Arg Thr His Arg Ala Ser Pro Leu Glu 275 280 285 Gly Leu Tyr Ala Arg Gly Met Glu Thr Leu Glu Leu Glu Thr His Arg 290 295 300 Ser Glu Arg Ile Leu Glu Val Ala Leu Ala Arg Gly Gly Leu Tyr Ile 305 310 315 320 Leu Glu Pro Arg Pro His Glu Thr Arg Pro Gly Leu Tyr Gly Leu Tyr 325 330 335 Ser Glu Arg Thr His Arg Ile Leu Glu Ala Ser Pro Thr His Arg Gly 340 345 350 Leu Leu Glu Leu Tyr Ser Val Ala Leu Ile Leu Glu Ala Ser Pro Thr 355 360 365 His Arg Ala Ser Asn Cys Tyr Ser Ile Leu Glu Ala Ser Asn Val Ala 370 375 380 Leu Ile Leu Glu Gly Leu Asn Pro Arg Ala Ser Pro Gly Leu Tyr Ser 385 390 395 400 Glu Arg Thr Tyr Arg Ala Arg Gly Ser Glu Arg Gly Leu Gly Leu Leu 405 410 415 Glu Ala Ser Asn Leu Glu Val Ala Leu Ile Leu Glu Ile Leu Glu Gly 420 425 430 Leu Tyr Pro Arg Ser Glu Arg Ala Leu Ala Ala Ser Pro Ile Leu Glu 435 440 445 Ile Leu Glu Gly Leu Asn Pro His Glu Gly Leu Cys Tyr Ser Leu Tyr 450 455 460 Ser Ser Glu Arg Pro His Glu Gly Leu Tyr His Ile Ser Gly Leu Val 465 470 475 480 Ala Leu Leu Glu Ala Ser Asn Leu Glu Thr His Arg Ala Arg Gly Ala 485 490 495 Ser Asn Gly Leu Tyr Thr Tyr Arg Gly Leu Tyr Ser Glu Arg Thr His 500 505 510 Arg Gly Leu Asn Thr Tyr Arg Ile Leu Glu Ala Arg Gly Pro His Glu 515 520 525 Ser Glu Arg Pro Arg Ala Ser Pro Pro His Glu Thr His Arg Pro His 530 535 540 Glu Gly Leu Tyr Pro His Glu Gly Leu Gly Leu Ser Glu Arg Leu Glu 545 550 555 560 Gly Leu Val Ala Leu Ala Ser Pro Thr His Arg Ala Ser Asn Pro Arg 565 570 575 Leu Glu Leu Glu Gly Leu Tyr Ala Leu Ala Gly Leu Tyr Leu Tyr Ser 580 585 590 Pro His Glu Ala Leu Ala Thr His Arg Ala Ser Pro Pro Arg Ala Leu 595 600 605 Ala Val Ala Leu Thr His Arg Leu Glu Ala Leu Ala His Ile Ser Gly 610 615 620 Leu Leu Glu Ile Leu Glu His Ile Ser Ala Leu Ala Gly Leu Tyr His 625 630 635 640 Ile Ser Ala Arg Gly Leu Glu Thr Tyr Arg Gly Leu Tyr Ile Leu Glu 645 650 655 Ala Leu Ala Ile Leu Glu Ala Ser Asn Pro Arg Ala Ser Asn Ala Arg 660 665 670 Gly Val Ala Leu Pro His Glu Leu Tyr Ser Val Ala Leu Ala Ser Asn 675 680 685 Thr His Arg Ala Ser Asn Ala Leu Ala Thr Tyr Arg Thr Tyr Arg Gly 690 695 700 Leu Met Glu Thr Ser Glu Arg Gly Leu Tyr Leu Glu Gly Leu Val Ala 705 710 715 720 Leu Ser Glu Arg Pro His Glu Gly Leu Gly Leu Leu Glu Ala Arg Gly 725 730 735 Thr His Arg Pro His Glu Gly Leu Tyr Gly Leu Tyr His Ile Ser Ala 740 745 750 Ser Pro Ala Leu Ala Leu Tyr Ser Pro His Glu Ile Leu Glu Ala Ser 755 760 765 Pro Ser Glu Arg Leu Glu Gly Leu Asn Gly Leu Ala Ser Asn Gly Leu 770 775 780 Pro His Glu Ala Arg Gly Leu Glu Thr Tyr Arg Thr Tyr Arg Thr Tyr 785 790 795 800 Arg Ala Ser Asn Leu Tyr Ser Pro His Glu Leu Tyr Ser Ala Ser Pro 805 810 815 Ile Leu Glu Ala Leu Ala Ser Glu Arg Thr His Arg Leu Glu Ala Ser 820 825 830 Asn Leu Tyr Ser Ala Leu Ala Leu Tyr Ser Ser Glu Arg Ile Leu Glu 835 840 845 Val Ala Leu Gly Leu Tyr Thr His Arg Thr His Arg Ala Leu Ala Ser 850 855 860 Glu Arg Leu Glu Gly Leu Asn Thr Tyr Arg Met Glu Thr Leu Tyr Ser 865 870 875 880 Ala Ser Asn Val Ala Leu Pro His Glu Leu Tyr Ser Gly Leu Leu Tyr 885 890 895 Ser Thr Tyr Arg Leu Glu Leu Glu Ser Glu Arg Gly Leu Ala Ser Pro 900 905 910 Thr His Arg Ser Glu Arg Gly Leu Tyr Leu Tyr Ser Pro His Glu Ser 915 920 925 Glu Arg Val Ala Leu Ala Ser Pro Leu Tyr Ser Leu Glu Leu Tyr Ser 930 935 940 Pro His Glu Ala Ser Pro Leu Tyr Ser Leu Glu Thr Tyr Arg Leu Tyr 945 950 955 960 Ser Met Glu Thr Leu Glu Thr His Arg Gly Leu Ile Leu Glu Thr Tyr 965 970 975 Arg Thr His Arg Gly Leu Ala Ser Pro Ala Ser Asn Pro His Glu Val 980 985 990 Ala Leu Leu Tyr Ser Pro His Glu Pro His Glu Leu Tyr Ser Val Ala 995 1000 1005 Leu Leu Glu Ala Ser Asn Ala Arg Gly Leu Tyr Ser Thr His Arg Thr 1010 1015 1020 Tyr Arg Leu Glu Ala Ser Asn Pro His Glu Ala Ser Pro Leu Tyr Ser 1025 1030 1035 1040 Ala Leu Ala Val Ala Leu Pro His Glu Leu Tyr Ser Ile Leu Glu Ala 1045 1050 1055 Ser Asn Ile Leu Glu Val Ala Leu Pro Arg Leu Tyr Ser Val Ala Leu 1060 1065 1070 Ala Ser Asn Thr Tyr Arg Thr His Arg Ile Leu Glu Thr Tyr Arg Ala 1075 1080 1085 Ser Pro Gly Leu Tyr Pro His Glu Ala Ser Asn Leu Glu Ala Arg Gly 1090 1095 1100 Ala Ser Asn Thr His Arg Ala Ser Asn Leu Glu Ala Leu Ala Ala Leu 1105 1110 1115 1120 Ala Ala Ser Asn Pro His Glu Ala Ser Asn Gly Leu Tyr Gly Leu Asn 1125 1130 1135 Ala Ser Asn Thr His Arg Gly Leu Ile Leu Glu Ala Ser Asn Ala Ser 1140 1145 1150 Asn Met Glu Thr Ala Ser Asn Pro His Glu Thr His Arg Leu Tyr Ser 1155 1160 1165 Leu Glu Leu Tyr Ser Ala Ser Asn Pro His Glu Thr His Arg Gly Leu 1170 1175 1180 Tyr Leu Glu Pro His Glu Gly Leu Pro His Glu Thr Tyr Arg Leu Tyr 1185 1190 1195 1200 Ser Leu Glu Leu Glu Cys Tyr Ser Val Ala Leu Ala Arg Gly Gly Leu 1205 1210 1215 Tyr Ile Leu Glu Ile Leu Glu Thr His Arg Ser Glu Arg Leu Tyr Ser 1220 1225 1230 Thr His Arg Leu Tyr Ser Ser Glu Arg Leu Glu Ala Ser Pro Leu Tyr 1235 1240 1245 Ser Gly Leu Tyr Thr Tyr Arg Ala Ser Asn Leu Tyr Ser Ala Leu Ala 1250 1255 1260 Leu Glu Ala Ser Asn Ala Ser Pro Leu Glu Cys Tyr Ser Ile Leu Glu 1265 1270 1275 1280 Leu Tyr Ser Val Ala Leu Ala Ser Asn Ala Ser Asn Thr Arg Pro Ala 1285 1290 1295 Ser Pro Leu Glu Pro His Glu Pro His Glu Ser Glu Arg Pro Arg Ser 1300 1305 1310 Glu Arg Gly Leu Ala Ser Pro Ala Ser Asn Pro His Glu Thr His Arg 1315 1320 1325 Ala Ser Asn Ala Ser Pro Leu Glu Ala Ser Asn Leu Tyr Ser Gly Leu 1330 1335 1340 Tyr Gly Leu Gly Leu Ile Leu Glu Thr His Arg Ser Glu Arg Ala Ser 1345 1350 1355 1360 Pro Thr His Arg Ala Ser Asn Ile Leu Glu Gly Leu Ala Leu Ala Ala 1365 1370 1375 Leu Ala Gly Leu Gly Leu Ala Ser Asn Ile Leu Glu Ser Glu Arg Leu 1380 1385 1390 Glu Ala Ser Pro Leu Glu Ile Leu Glu Gly Leu Asn Gly Leu Asn Thr 1395 1400 1405 Tyr Arg Thr Tyr Arg Leu Glu Thr His Arg Pro His Glu Ala Ser Asn 1410 1415 1420 Pro His Glu Ala Ser Pro Ala Ser Asn Gly Leu Pro Arg Gly Leu Ala 1425 1430 1435 1440 Ser Asn Ile Leu Glu Ser Glu Arg Ile Leu Glu Gly Leu Ala Ser Asn 1445 1450 1455 Leu Glu Ser Glu Arg Ser Glu Arg Ala Ser Pro Ile Leu Glu Ile Leu 1460 1465 1470 Glu Gly Leu Tyr Gly Leu Asn Leu Glu Gly Leu Leu Glu Met Glu Thr 1475 1480 1485 Pro Arg Ala Ser Asn Ile Leu Glu Gly Leu Ala Arg Gly Pro His Glu 1490 1495 1500 Pro Arg Ala Ser Asn Gly Leu Tyr Leu Tyr Ser Leu Tyr Ser Thr Tyr 1505 1510 1515 1520 Arg Gly Leu Leu Glu Ala Ser Pro Leu Tyr Ser Thr Tyr Arg Thr His 1525 1530 1535 Arg Met Glu Thr Pro His Glu His Ile Ser Thr Tyr Arg Leu Glu Ala 1540 1545 1550 Arg Gly Ala Leu Ala Gly Leu Asn Gly Leu Pro His Glu Gly Leu His 1555 1560 1565 Ile Ser Gly Leu Tyr Leu Tyr Ser Ser Glu Arg Ala Arg Gly Ile Leu 1570 1575 1580 Glu Ala Leu Ala Leu Glu Thr His Arg Ala Ser Asn Ser Glu Arg Val 1585 1590 1595 1600 Ala Leu Ala Ser Asn Gly Leu Ala Leu Ala Leu Glu Leu Glu Ala Ser 1605 1610 1615 Asn Pro Arg Ser Glu Arg Ala Arg Gly Val Ala Leu Thr Tyr Arg Thr 1620 1625 1630 His Arg Pro His Glu Pro His Glu Ser Glu Arg Ser Glu Arg Ala Ser 1635 1640 1645 Pro Thr Tyr Arg Val Ala Leu Leu Tyr Ser Leu Tyr Ser Val Ala Leu 1650 1655 1660 Ala Ser Asn Leu Tyr Ser Ala Leu Ala Thr His Arg Gly Leu Ala Leu 1665 1670 1675 1680 Ala Ala Leu Ala Met Glu Thr Pro His Glu Leu Glu Gly Leu Tyr Thr 1685 1690 1695 Arg Pro Val Ala Leu Gly Leu Gly Leu Asn Leu Glu Val Ala Leu Thr 1700 1705 1710 Tyr Arg Ala Ser Pro Pro His Glu Thr His Arg Ala Ser Pro Gly Leu 1715 1720 1725 Thr His Arg Ser Glu Arg Gly Leu Val Ala Leu Ser Glu Arg Thr His 1730 1735 1740 Arg Thr His Arg Ala Ser Pro Leu Tyr Ser Ile Leu Glu Ala Leu Ala 1745 1750 1755 1760 Ala Ser Pro Ile Leu Glu Thr His Arg Ile Leu Glu Ile Leu Glu Ile 1765 1770 1775 Leu Glu Pro Arg Thr Tyr Arg Ile Leu Glu Gly Leu Tyr Pro Arg Ala 1780 1785 1790 Leu Ala Leu Glu Ala Ser Asn Ile Leu Glu Gly Leu Tyr Ala Ser Asn 1795 1800 1805 Met Glu Thr Leu Glu Thr Tyr Arg Leu Tyr Ser Ala Ser Pro Ala Ser 1810 1815 1820 Pro Pro His Glu Val Ala Leu Gly Leu Tyr Ala Leu Ala Leu Glu Ile 1825 1830 1835 1840 Leu Glu Pro His Glu Ser Glu Arg Gly Leu Tyr Ala Leu Ala Val Ala 1845 1850 1855 Leu Ile Leu Glu Leu Glu Leu Glu Gly Leu Pro His Glu Ile Leu Glu 1860 1865 1870 Pro Arg Gly Leu Ile Leu Glu Ala Leu Ala Ile Leu Glu Pro Arg Val 1875 1880 1885 Ala Leu Leu Glu Gly Leu Tyr Thr His Arg Pro His Glu Ala Leu Ala 1890 1895 1900 Leu Glu Val Ala Leu Ser Glu Arg Thr Tyr Arg Ile Leu Glu Ala Leu 1905 1910 1915 1920 Ala Ala Ser Asn Leu Tyr Ser Val Ala Leu Leu Glu Thr His Arg Val 1925 1930 1935 Ala Leu Gly Leu Asn Thr His Arg Ile Leu Glu Ala Ser Pro Ala Ser 1940 1945 1950 Asn Ala Leu Ala Leu Glu Ser Glu Arg Leu Tyr Ser Ala Arg Gly Ala 1955 1960 1965 Ser Asn Gly Leu Leu Tyr Ser Thr Arg Pro Ala Ser Pro Gly Leu Val 1970 1975 1980 Ala Leu Thr Tyr Arg Leu Tyr Ser Thr Tyr Arg Ile Leu Glu Val Ala 1985 1990 1995 2000 Leu Thr His Arg Ala Ser Asn Thr Arg Pro Leu Glu Ala Leu Ala Leu 2005 2010 2015 Tyr Ser Val Ala Leu Ala Ser Asn Thr His Arg Gly Leu Asn Ile Leu 2020 2025 2030 Glu Ala Ser Pro Leu Glu Ile Leu Glu Ala Arg Gly Leu Tyr Ser Leu 2035 2040 2045 Tyr Ser Met Glu Thr Leu Tyr Ser Gly Leu Ala Leu Ala Leu Glu Gly 2050 2055 2060 Leu Ala Ser Asn Gly Leu Asn Ala Leu Ala Gly Leu Ala Leu Ala Thr 2065 2070 2075 2080 His Arg Leu Tyr Ser Ala Leu Ala Ile Leu Glu Ile Leu Glu Ala Ser 2085 2090 2095 Asn Thr Tyr Arg Gly Leu Asn Thr Tyr Arg Ala Ser Asn Gly Leu Asn 2100 2105 2110 Thr Tyr Arg Thr His Arg Gly Leu Gly Leu Gly Leu Leu Tyr Ser Ala 2115 2120 2125 Ser Asn Ala Ser Asn Ile Leu Glu Ala Ser Asn Pro His Glu Ala Ser 2130 2135 2140 Asn Ile Leu Glu Ala Ser Pro Ala Ser Pro Leu Glu Ser Glu Arg Ser 2145 2150 2155 2160 Glu Arg Leu Tyr Ser Leu Glu Ala Ser Asn Gly Leu Ser Glu Arg Ile 2165 2170 2175 Leu Glu Ala Ser Asn Leu Tyr Ser Ala Leu Ala Met Glu Thr Ile Leu 2180 2185 2190 Glu Ala Ser Asn Ile Leu Glu Ala Ser Asn Leu Tyr Ser Pro His Glu 2195 2200 2205 Leu Glu Ala Ser Asn Gly Leu Asn Cys Tyr Ser Ser Glu Arg Val Ala 2210 2215 2220 Leu Ser Glu Arg Thr Tyr Arg Leu Glu Met Glu Thr Ala Ser Asn Ser 2225 2230 2235 2240 Glu Arg Met Glu Thr Ile Leu Glu Pro Arg Thr Tyr Arg Gly Leu Tyr 2245 2250 2255 Val Ala Leu Leu Tyr Ser Ala Arg Gly Leu Glu Gly Leu Ala Ser Pro 2260 2265 2270 Pro His Glu Ala Ser Pro Ala Leu Ala Ser Glu Arg Leu Glu Leu Tyr 2275 2280 2285 Ser Ala Ser Pro Ala Leu Ala Leu Glu Leu Glu Leu Tyr Ser Thr Tyr 2290 2295 2300 Arg Ile Leu Glu Thr Tyr Arg Ala Ser Pro Ala Ser Asn Ala Arg Gly 2305 2310 2315 2320 Gly Leu Tyr Thr His Arg Leu Glu Ile Leu Glu Gly Leu Tyr Gly Leu 2325 2330 2335 Asn Val Ala Leu Ala Ser Pro Ala Arg Gly Leu Glu Leu Tyr Ser Ala 2340 2345 2350 Ser Pro Leu Tyr Ser Val Ala Leu Ala Ser Asn Ala Ser Asn Thr His 2355 2360 2365 Arg Leu Glu Ser Glu Arg Thr His Arg Ala Ser Pro Ile Leu Glu Pro 2370 2375 2380 Arg Pro His Glu Gly Leu Asn Leu Glu Ser Glu Arg Leu Tyr Ser Thr 2385 2390 2395 2400 Tyr Arg Val Ala Leu Ala Ser Pro Ala Ser Asn Gly Leu Asn Ala Arg 2405 2410 2415 Gly Leu Glu Leu Glu Ser Glu Arg Thr His Arg Pro His Glu Thr His 2420 2425 2430 Arg Gly Leu Thr Tyr Arg Ile Leu Glu Leu Tyr Ser Ala Ser Asn Ile 2435 2440 2445 Leu Glu Ile Leu Glu Ala Ser Asn Thr His Arg Ser Glu Arg Ile Leu 2450 2455 2460 Glu Leu Glu Ala Ser Asn Leu Glu Ala Arg Gly Thr Tyr Arg Gly Leu 2465 2470 2475 2480 Ser Glu Arg Ala Ser Asn His Ile Ser Leu Glu Ile Leu Glu Ala Ser 2485 2490 2495 Pro Leu Glu Ser Glu Arg Ala Arg Gly Thr Tyr Arg Ala Leu Ala Ser 2500 2505 2510 Glu Arg Leu Tyr Ser Ile Leu Glu Ala Ser Asn Ile Leu Glu Gly Leu 2515 2520 2525 Tyr Ser Glu Arg Leu Tyr Ser Val Ala Leu Ala Ser Asn Pro His Glu 2530 2535 2540 Ala Ser Pro Pro Arg Ile Leu Glu Ala Ser Pro Leu Tyr Ser Ala Ser 2545 2550 2555 2560 Asn Gly Leu Asn Ile Leu Glu Gly Leu Asn Leu Glu Pro His Glu Ala 2565 2570 2575 Ser Asn Leu Glu Gly Leu Ser Glu Arg Ser Glu Arg Leu Tyr Ser Ile 2580 2585 2590 Leu Glu Gly Leu Val Ala Leu Ile Leu Glu Leu Glu Leu Tyr Ser Ala 2595 2600 2605 Ser Asn Ala Leu Ala Ile Leu Glu Val Ala Leu Thr Tyr Arg Ala Ser 2610 2615 2620 Asn Ser Glu Arg Met Glu Thr Thr Tyr Arg Gly Leu Ala Ser Asn Pro 2625 2630 2635 2640 His Glu Ser Glu Arg Thr His Arg Ser Glu Arg Pro His Glu Thr Arg 2645 2650 2655 Pro Ile Leu Glu Ala Arg Gly Ile Leu Glu Pro Arg Leu Tyr Ser Thr 2660 2665 2670 Tyr Arg Pro His Glu Ala Ser Asn Ser Glu Arg Ile Leu Glu Ser Glu 2675 2680 2685 Arg Leu Glu Ala Ser Asn Ala Ser Asn Gly Leu Thr Tyr Arg Thr His 2690 2695 2700 Arg Ile Leu Glu Ile Leu Glu Ala Ser Asn Cys Tyr Ser Met Glu Thr 2705 2710 2715 2720 Gly Leu Ala Ser Asn Ala Ser Asn Ser Glu Arg Gly Leu Tyr Thr Arg 2725 2730 2735 Pro Leu Tyr Ser Val Ala Leu Ser Glu Arg Leu Glu Ala Ser Asn Thr 2740 2745 2750 Tyr Arg Gly Leu Tyr Gly Leu Ile Leu Glu Ile Leu Glu Thr Arg Pro 2755 2760 2765 Thr His Arg Leu Glu Gly Leu Asn Ala Ser Pro Thr His Arg Gly Leu 2770 2775 2780 Asn Gly Leu Ile Leu Glu Leu Tyr Ser Gly Leu Asn Ala Arg Gly Val 2785 2790 2795 2800 Ala Leu Val Ala Leu Pro His Glu Leu Tyr Ser Thr Tyr Arg Ser Glu 2805 2810 2815 Arg Gly Leu Asn Met Glu Thr Ile Leu Glu Ala Ser Asn Ile Leu Glu 2820 2825 2830 Ser Glu Arg Ala Ser Pro Thr Tyr Arg Ile Leu Glu Ala Ser Asn Ala 2835 2840 2845 Arg Gly Thr Arg Pro Ile Leu Glu Pro His Glu Val Ala Leu Thr His 2850 2855 2860 Arg Ile Leu Glu Thr His Arg Ala Ser Asn Ala Ser Asn Ala Arg Gly 2865 2870 2875 2880 Leu Glu Ala Ser Asn Ala Ser Asn Ser Glu Arg Leu Tyr Ser Ile Leu 2885 2890 2895 Glu Thr Tyr Arg Ile Leu Glu Ala Ser Asn Gly Leu Tyr Ala Arg Gly 2900 2905 2910 Leu Glu Ile Leu Glu Ala Ser Pro Gly Leu Asn Leu Tyr Ser Pro Arg 2915 2920 2925 Ile Leu Glu Ser Glu Arg Ala Ser Asn Leu Glu Gly Leu Tyr Ala Ser 2930 2935 2940 Asn Ile Leu Glu His Ile Ser Ala Leu Ala Ser Glu Arg Ala Ser Asn 2945 2950 2955 2960 Ala Ser Asn Ile Leu Glu Met Glu Thr Pro His Glu Leu Tyr Ser Leu 2965 2970 2975 Glu Ala Ser Pro Gly Leu Tyr Cys Tyr Ser Ala Arg Gly Ala Ser Pro 2980 2985 2990 Thr His Arg His Ile Ser Ala Arg Gly Thr Tyr Arg Ile Leu Glu Thr 2995 3000 3005 Arg Pro Ile Leu Glu Leu Tyr Ser Thr Tyr Arg Pro His Glu Ala Ser 3010 3015 3020 Asn Leu Glu Pro His Glu Ala Ser Pro Leu Tyr Ser Gly Leu Leu Glu 3025 3030 3035 3040 Ala Ser Asn Gly Leu Leu Tyr Ser Gly Leu Ile Leu Glu Leu Tyr Ser 3045 3050 3055 Ala Ser Pro Leu Glu Thr Tyr Arg Ala Ser Pro Ala Ser Asn Gly Leu 3060 3065 3070 Asn Ser Glu Arg Ala Ser Asn Ser Glu Arg Gly Leu Tyr Ile Leu Glu 3075 3080 3085 Leu Glu Leu Tyr Ser Ala Ser Pro Pro His Glu Thr Arg Pro Gly Leu 3090 3095 3100 Tyr Ala Ser Pro Thr Tyr Arg Leu Glu Gly Leu Asn Thr Tyr Arg Ala 3105 3110 3115 3120 Ser Pro Leu Tyr Ser Pro Arg Thr Tyr Arg Thr Tyr Arg Met Glu Thr 3125 3130 3135 Leu Glu Ala Ser Asn Leu Glu Thr Tyr Arg Ala Ser Pro Pro Arg Ala 3140 3145 3150 Ser Asn Leu Tyr Ser Thr Tyr Arg Val Ala Leu Ala Ser Pro Val Ala 3155 3160 3165 Leu Ala Ser Asn Ala Ser Asn Val Ala Leu Gly Leu Tyr Ile Leu Glu 3170 3175 3180 Ala Arg Gly Gly Leu Tyr Thr Tyr Arg Met Glu Thr Thr Tyr Arg Leu 3185 3190 3195 3200 Glu Leu Tyr Ser Gly Leu Tyr Pro Arg Ala Arg Gly Gly Leu Tyr Ser 3205 3210 3215 Glu Arg Val Ala Leu Met Glu Thr Thr His Arg Thr His Arg Ala Ser 3220 3225 3230 Asn Ile Leu Glu Thr Tyr Arg Leu Glu Ala Ser Asn Ser Glu Arg Ser 3235 3240 3245 Glu Arg Leu Glu Thr Tyr Arg Ala Arg Gly Gly Leu Tyr Thr His Arg 3250 3255 3260 Leu Tyr Ser Pro His Glu Ile Leu Glu Ile Leu Glu Leu Tyr Ser Leu 3265 3270 3275 3280 Tyr Ser Thr Tyr Arg Ala Leu Ala Ser Glu Arg Gly Leu Tyr Ala Ser 3285 3290 3295 Asn Leu Tyr Ser Ala Ser Pro Ala Ser Asn Ile Leu Glu Val Ala Leu 3300 3305 3310 Ala Arg Gly Ala Ser Asn Ala Ser Asn Ala Ser Pro Ala Arg Gly Val 3315 3320 3325 Ala Leu Thr Tyr Arg Ile Leu Glu Ala Ser Asn Val Ala Leu Val Ala 3330 3335 3340 Leu Val Ala Leu Leu Tyr Ser Ala Ser Asn Leu Tyr Ser Gly Leu Thr 3345 3350 3355 3360 Tyr Arg Ala Arg Gly Leu Glu Ala Leu Ala Thr His Arg Ala Ser Asn 3365 3370 3375 Ala Leu Ala Ser Glu Arg Gly Leu Asn Ala Leu Ala Gly Leu Tyr Val 3380 3385 3390 Ala Leu Gly Leu Leu Tyr Ser Ile Leu Glu Leu Glu Ser Glu Arg Ala 3395 3400 3405 Leu Ala Leu Glu Gly Leu Ile Leu Glu Pro Arg Ala Ser Pro Val Ala 3410 3415 3420 Leu Gly Leu Tyr Ala Ser Asn Leu Glu Ser Glu Arg Gly Leu Asn Val 3425 3430 3435 3440 Ala Leu Val Ala Leu Val Ala Leu Met Glu Thr Leu Tyr Ser Ser Glu 3445 3450 3455 Arg Leu Tyr Ser Ala Ser Asn Ala Ser Pro Gly Leu Asn Gly Leu Tyr 3460 3465 3470 Ile Leu Glu Thr His Arg Ala Ser Asn Leu Tyr Ser Cys Tyr Ser Leu 3475 3480 3485 Tyr Ser Met Glu Thr Ala Ser Asn Leu Glu Gly Leu Asn Ala Ser Pro 3490 3495 3500 Ala Ser Asn Ala Ser Asn Gly Leu Tyr Ala Ser Asn Ala Ser Pro Ile 3505 3510 3515 3520 Leu Glu Gly Leu Tyr Pro His Glu Ile Leu Glu Gly Leu Tyr Pro His 3525 3530 3535 Glu His Ile Ser Gly Leu Asn Pro His Glu Ala Ser Asn Ala Ser Asn 3540 3545 3550 Ile Leu Glu Ala Leu Ala Leu Tyr Ser Leu Glu Val Ala Leu Ala Leu 3555 3560 3565 Ala Ser Glu Arg Ala Ser Asn Thr Arg Pro Thr Tyr Arg Ala Ser Asn 3570 3575 3580 Ala Arg Gly Gly Leu Asn Ile Leu Glu Gly Leu Ala Arg Gly Ser Glu 3585 3590 3595 3600 Arg Ser Glu Arg Ala Arg Gly Thr His Arg Leu Glu Gly Leu Tyr Cys 3605 3610 3615 Tyr Ser Ser Glu Arg Thr Arg Pro Gly Leu Pro His Glu Ile Leu Glu 3620 3625 3630 Pro Arg Val Ala Leu Ala Ser Pro Ala Ser Pro Gly Leu Tyr Thr Arg 3635 3640 3645 Pro Gly Leu Tyr Gly Leu Ala Arg Gly Pro Arg Leu Glu 3650 3655 3660 <210> 3 <211> 3876 <212> DNA <213> Clostridium botulinum <400> 3 atgccagtta caataaataa ttttaattat aatgatccta ttgataataa taatattatt 60 atgatggagc ctccatttgc gagaggtacg gggagatatt ataaagcttt taaaatcaca 120 gatcgtattt ggataatacc ggaaagatat acttttggat ataaacctga ggattttaat 180 aaaagttccg gtatttttaa tagagatgtt tgtgaatatt atgatccaga ttacttaaat 240 actaatgata aaaagaatat atttttacaa acaatgatca agttatttaa tagaatcaaa 300 tcaaaaccat tgggtgaaaa gttattagag atgattataa atggtatacc ttatcttgga 360 gatagacgtg ttccactcga agagtttaac acaaacattg ctagtgtaac tgttaataaa 420 ttaatcagta atccaggaga agtggagcga aaaaaaggta ttttcgcaaa tttaataata 480 tttggacctg ggccagtttt aaatgaaaat gagactatag atataggtat acaaaatcat 540 tttgcatcaa gggaaggctt cgggggtata atgcaaatga agttttgccc agaatatgta 600 agcgtattta ataatgttca agaaaacaaa ggcgcaagta tatttaatag acgtggatat 660 ttttcagatc cagccttgat attaatgcat gaacttatac atgttttaca tggattatat 720 ggcattaaag tagatgattt accaattgta ccaaatgaaa aaaaattttt tatgcaatct 780 acagatgcta tacaggcaga agaactatat acatttggag gacaagatcc cagcatcata 840 actccttcta cggataaaag tatctatgat aaagttttgc aaaattttag agggatagtt 900 gatagactta acaaggtttt agtttgcata tcagatccta acattaatat taatatatat 960 aaaaataaat ttaaagataa atataaattc gttgaagatt ctgagggaaa atatagtata 1020 gatgtagaaa gttttgataa attatataaa agcttaatgt ttggttttac agaaactaat 1080 atagcagaaa attataaaat aaaaactaga gcttcttatt ttagtgattc cttaccacca 1140 gtaaaaataa aaaatttatt agataatgaa atctatacta tagaggaagg gtttaatata 1200 tctgataaag atatggaaaa agaatataga ggtcagaata aagctataaa taaacaagct 1260 tatgaagaaa ttagcaagga gcatttggct gtatataaga tacaaatgtg taaaagtgtt 1320 aaagctccag gaatatgtat tgatgttgat aatgaagatt tgttctttat agctgataaa 1380 aatagttttt cagatgattt atctaaaaac gaaagaatag aatataatac acagagtaat 1440 tatatagaaa atgacttccc tataaatgaa ttaattttag atactgattt aataagtaaa 1500 atagaattac caagtgaaaa tacagaatca cttactgatt ttaatgtaga tgttccagta 1560 tatgaaaaac aacccgctat aaaaaaaatt tttacagatg aaaataccat ctttcaatat 1620 ttatactctc agacatttcc tctagatata agagatataa gtttaacatc ttcatttgat 1680 gatgcattat tattttctaa caaagtttat tcattttttt ctatggatta tattaaaact 1740 gctaataaag tggtagaagc aggattattt gcaggttggg tgaaacagat agtaaatgat 1800 tttgtaatcg aagctaataa aagcaatact atggataaaa ttgcagatat atctctaatt 1860 gttccttata taggattagc tttaaatgta ggaaatgaaa cagctaaagg aaattttgaa 1920 aatgcttttg agattgcagg agccagtatt ctactagaat ttataccaga acttttaata 1980 cctgtagttg gagccttttt attagaatca tatattgaca ataaaaataa aattattaaa 2040 acaatagata atgctttaac taaaagaaat gaaaaatgga gtgatatgta cggattaata 2100 gtagcgcaat ggctctcaac agttaatact caattttata caataaaaga gggaatgtat 2160 aaggctttaa attatcaagc acaagcattg gaagaaataa taaaatacag atataatata 2220 tattctgaaa aagaaaagtc aaatattaac atcgatttta atgatataaa ttctaaactt 2280 aatgagggta ttaaccaagc tatagataat ataaataatt ttataaatgg atgttctgta 2340 tcatatttaa tgaaaaaaat gattccatta gctgtagaaa aattactaga ctttgataat 2400 actctcaaaa aaaatttgtt aaattatata gatgaaaata aattatattt gattggaagt 2460 gcagaatatg aaaaatcaaa agtaaataaa tacttgaaaa ccattatgcc gtttgatctt 2520 tcaatatata ccaatgatac aatactaata gaaatgttta ataaatataa tagcgaaatt 2580 ttaaataata ttatcttaaa tttaagatat aaggataata atttaataga tttatcagga 2640 tatggggcaa aggtagaggt atatgatgga gtcgagctta atgataaaaa tcaatttaaa 2700 ttaactagtt cagcaaatag taagattaga gtgactcaaa atcagaatat catatttaat 2760 agtgtgttcc ttgattttag cgttagcttt tggataagaa tacctaaata taagaatgat 2820 ggtatacaaa attatattca taatgaatat acaataatta attgtatgaa aaataattcg 2880 ggctggaaaa tatctattag gggtaatagg ataatatgga ctttaattga tataaatgga 2940 aaaaccaaat cggtattttt tgaatataac ataagagaag atatatcaga gtatataaat 3000 agatggtttt ttgtaactat tactaataat ttgaataacg ctaaaattta tattaatggt 3060 aagctagaat caaatacaga tattaaagat ataagagaag ttattgctaa tggtgaaata 3120 atatttaaat tagatggtga tatagataga acacaattta tttggatgaa atatttcagt 3180 atttttaata cggaattaag tcaatcaaat attgaagaaa gatataaaat tcaatcatat 3240 agcgaatatt taaaagattt ttggggaaat cctttaatgt acaataaaga atattatatg 3300 tttaatgcgg ggaataaaaa ttcatatatt aaactaaaga aagattcacc tgtaggtgaa 3360 attttaacac gtagcaaata taatcaaaat tctaaatata taaattatag agatttatat 3420 attggagaaa aatttattat aagaagaaag tcaaattctc aatctataaa tgatgatata 3480 gttagaaaag aagattatat atatctagat ttttttaatt taaatcaaga gtggagagta 3540 tatacctata aatattttaa gaaagaggaa gaaaaattgt ttttagctcc tataagtgat 3600 tctgatgagt tttacaatac tatacaaata aaagaatatg atgaacagcc aacatatagt 3660 tgtcagttgc tttttaaaaa agatgaagaa agtactgatg agataggatt gattggtatt 3720 catcgtttct acgaatctgg aattgtattt gaagagtata aagattattt ttgtataagt 3780 aaatggtact taaaagaggt aaaaaggaaa ccatataatt taaaattggg atgtaattgg 3840 cagtttattc ctaaagatga agggtggact gaataa 3876 <210> 4 <211> 3642 <212> PRT <213> Clostridium botulinum <400> 4 Met Glu Thr Pro Arg Val Ala Leu Thr His Arg Ile Leu Glu Ala Ser 1 5 10 15 Asn Ala Ser Asn Pro His Glu Ala Ser Asn Thr Tyr Arg Ala Ser Asn 20 25 30 Ala Ser Pro Pro Arg Ile Leu Glu Ala Ser Pro Ala Ser Asn Ala Ser 35 40 45 Asn Ala Ser Asn Ile Leu Glu Ile Leu Glu Met Glu Thr Met Glu Thr 50 55 60 Gly Leu Pro Arg Pro Arg Pro His Glu Ala Leu Ala Ala Arg Gly Gly 65 70 75 80 Leu Tyr Thr His Arg Gly Leu Tyr Ala Arg Gly Thr Tyr Arg Thr Tyr 85 90 95 Arg Leu Tyr Ser Ala Leu Ala Pro His Glu Leu Tyr Ser Ile Leu Glu 100 105 110 Thr His Arg Ala Ser Pro Ala Arg Gly Ile Leu Glu Thr Arg Pro Ile 115 120 125 Leu Glu Ile Leu Glu Pro Arg Gly Leu Ala Arg Gly Thr Tyr Arg Thr 130 135 140 His Arg Pro His Glu Gly Leu Tyr Thr Tyr Arg Leu Tyr Ser Pro Arg 145 150 155 160 Gly Leu Ala Ser Pro Pro His Glu Ala Ser Asn Leu Tyr Ser Ser Glu 165 170 175 Arg Ser Glu Arg Gly Leu Tyr Ile Leu Glu Pro His Glu Ala Ser Asn 180 185 190 Ala Arg Gly Ala Ser Pro Val Ala Leu Cys Tyr Ser Gly Leu Thr Tyr 195 200 205 Arg Thr Tyr Arg Ala Ser Pro Pro Arg Ala Ser Pro Thr Tyr Arg Leu 210 215 220 Glu Ala Ser Asn Thr His Arg Ala Ser Asn Ala Ser Pro Leu Tyr Ser 225 230 235 240 Leu Tyr Ser Ala Ser Asn Ile Leu Glu Pro His Glu Leu Glu Gly Leu 245 250 255 Asn Thr His Arg Met Glu Thr Ile Leu Glu Leu Tyr Ser Leu Glu Pro 260 265 270 His Glu Ala Ser Asn Ala Arg Gly Ile Leu Glu Leu Tyr Ser Ser Glu 275 280 285 Arg Leu Tyr Ser Pro Arg Leu Glu Gly Leu Tyr Gly Leu Leu Tyr Ser 290 295 300 Leu Glu Leu Glu Gly Leu Met Glu Thr Ile Leu Glu Ile Leu Glu Ala 305 310 315 320 Ser Asn Gly Leu Tyr Ile Leu Glu Pro Arg Thr Tyr Arg Leu Glu Gly 325 330 335 Leu Tyr Ala Ser Pro Ala Arg Gly Ala Arg Gly Val Ala Leu Pro Arg 340 345 350 Leu Glu Gly Leu Gly Leu Pro His Glu Ala Ser Asn Thr His Arg Ala 355 360 365 Ser Asn Ile Leu Glu Ala Leu Ala Ser Glu Arg Val Ala Leu Thr His 370 375 380 Arg Val Ala Leu Ala Ser Asn Leu Tyr Ser Leu Glu Ile Leu Glu Ser 385 390 395 400 Glu Arg Ala Ser Asn Pro Arg Gly Leu Tyr Gly Leu Val Ala Leu Gly 405 410 415 Leu Ala Arg Gly Leu Tyr Ser Leu Tyr Ser Gly Leu Tyr Ile Leu Glu 420 425 430 Pro His Glu Ala Leu Ala Ala Ser Asn Leu Glu Ile Leu Glu Ile Leu 435 440 445 Glu Pro His Glu Gly Leu Tyr Pro Arg Gly Leu Tyr Pro Arg Val Ala 450 455 460 Leu Leu Glu Ala Ser Asn Gly Leu Ala Ser Asn Gly Leu Thr His Arg 465 470 475 480 Ile Leu Glu Ala Ser Pro Ile Leu Glu Gly Leu Tyr Ile Leu Glu Gly 485 490 495 Leu Asn Ala Ser Asn His Ile Ser Pro His Glu Ala Leu Ala Ser Glu 500 505 510 Arg Ala Arg Gly Gly Leu Gly Leu Tyr Pro His Glu Gly Leu Tyr Gly 515 520 525 Leu Tyr Ile Leu Glu Met Glu Thr Gly Leu Asn Met Glu Thr Leu Tyr 530 535 540 Ser Pro His Glu Cys Tyr Ser Pro Arg Gly Leu Thr Tyr Arg Val Ala 545 550 555 560 Leu Ser Glu Arg Val Ala Leu Pro His Glu Ala Ser Asn Ala Ser Asn 565 570 575 Val Ala Leu Gly Leu Asn Gly Leu Ala Ser Asn Leu Tyr Ser Gly Leu 580 585 590 Tyr Ala Leu Ala Ser Glu Arg Ile Leu Glu Pro His Glu Ala Ser Asn 595 600 605 Ala Arg Gly Ala Arg Gly Gly Leu Tyr Thr Tyr Arg Pro His Glu Ser 610 615 620 Glu Arg Ala Ser Pro Pro Arg Ala Leu Ala Leu Glu Ile Leu Glu Leu 625 630 635 640 Glu Met Glu Thr His Ile Ser Gly Leu Leu Glu Ile Leu Glu His Ile 645 650 655 Ser Val Ala Leu Leu Glu His Ile Ser Gly Leu Tyr Leu Glu Thr Tyr 660 665 670 Arg Gly Leu Tyr Ile Leu Glu Leu Tyr Ser Val Ala Leu Ala Ser Pro 675 680 685 Ala Ser Pro Leu Glu Pro Arg Ile Leu Glu Val Ala Leu Pro Arg Ala 690 695 700 Ser Asn Gly Leu Leu Tyr Ser Leu Tyr Ser Pro His Glu Pro His Glu 705 710 715 720 Met Glu Thr Gly Leu Asn Ser Glu Arg Thr His Arg Ala Ser Pro Ala 725 730 735 Leu Ala Ile Leu Glu Gly Leu Asn Ala Leu Ala Gly Leu Gly Leu Leu 740 745 750 Glu Thr Tyr Arg Thr His Arg Pro His Glu Gly Leu Tyr Gly Leu Tyr 755 760 765 Gly Leu Asn Ala Ser Pro Pro Arg Ser Glu Arg Ile Leu Glu Ile Leu 770 775 780 Glu Thr His Arg Pro Arg Ser Glu Arg Thr His Arg Ala Ser Pro Leu 785 790 795 800 Tyr Ser Ser Glu Arg Ile Leu Glu Thr Tyr Arg Ala Ser Pro Leu Tyr 805 810 815 Ser Val Ala Leu Leu Glu Gly Leu Asn Ala Ser Asn Pro His Glu Ala 820 825 830 Arg Gly Gly Leu Tyr Ile Leu Glu Val Ala Leu Ala Ser Pro Ala Arg 835 840 845 Gly Leu Glu Ala Ser Asn Leu Tyr Ser Val Ala Leu Leu Glu Val Ala 850 855 860 Leu Cys Tyr Ser Ile Leu Glu Ser Glu Arg Ala Ser Pro Pro Arg Ala 865 870 875 880 Ser Asn Ile Leu Glu Ala Ser Asn Ile Leu Glu Ala Ser Asn Ile Leu 885 890 895 Glu Thr Tyr Arg Leu Tyr Ser Ala Ser Asn Leu Tyr Ser Pro His Glu 900 905 910 Leu Tyr Ser Ala Ser Pro Leu Tyr Ser Thr Tyr Arg Leu Tyr Ser Pro 915 920 925 His Glu Val Ala Leu Gly Leu Ala Ser Pro Ser Glu Arg Gly Leu Gly 930 935 940 Leu Tyr Leu Tyr Ser Thr Tyr Arg Ser Glu Arg Ile Leu Glu Ala Ser 945 950 955 960 Pro Val Ala Leu Gly Leu Ser Glu Arg Pro His Glu Ala Ser Pro Leu 965 970 975 Tyr Ser Leu Glu Thr Tyr Arg Leu Tyr Ser Ser Glu Arg Leu Glu Met 980 985 990 Glu Thr Pro His Glu Gly Leu Tyr Pro His Glu Thr His Arg Gly Leu 995 1000 1005 Thr His Arg Ala Ser Asn Ile Leu Glu Ala Leu Ala Gly Leu Ala Ser 1010 1015 1020 Asn Thr Tyr Arg Leu Tyr Ser Ile Leu Glu Leu Tyr Ser Thr His Arg 1025 1030 1035 1040 Ala Arg Gly Ala Leu Ala Ser Glu Arg Thr Tyr Arg Pro His Glu Ser 1045 1050 1055 Glu Arg Ala Ser Pro Ser Glu Arg Leu Glu Pro Arg Pro Arg Val Ala 1060 1065 1070 Leu Leu Tyr Ser Ile Leu Glu Leu Tyr Ser Ala Ser Asn Leu Glu Leu 1075 1080 1085 Glu Ala Ser Pro Ala Ser Asn Gly Leu Ile Leu Glu Thr Tyr Arg Thr 1090 1095 1100 His Arg Ile Leu Glu Gly Leu Gly Leu Gly Leu Tyr Pro His Glu Ala 1105 1110 1115 1120 Ser Asn Ile Leu Glu Ser Glu Arg Ala Ser Pro Leu Tyr Ser Ala Ser 1125 1130 1135 Pro Met Glu Thr Gly Leu Leu Tyr Ser Gly Leu Thr Tyr Arg Ala Arg 1140 1145 1150 Gly Gly Leu Tyr Gly Leu Asn Ala Ser Asn Leu Tyr Ser Ala Leu Ala 1155 1160 1165 Ile Leu Glu Ala Ser Asn Leu Tyr Ser Gly Leu Asn Ala Leu Ala Thr 1170 1175 1180 Tyr Arg Gly Leu Gly Leu Ile Leu Glu Ser Glu Arg Leu Tyr Ser Gly 1185 1190 1195 1200 Leu His Ile Ser Leu Glu Ala Leu Ala Val Ala Leu Thr Tyr Arg Leu 1205 1210 1215 Tyr Ser Ile Leu Glu Gly Leu Asn Met Glu Thr Cys Tyr Ser Leu Tyr 1220 1225 1230 Ser Ser Glu Arg Val Ala Leu Leu Tyr Ser Ala Leu Ala Pro Arg Gly 1235 1240 1245 Leu Tyr Ile Leu Glu Cys Tyr Ser Ile Leu Glu Ala Ser Pro Val Ala 1250 1255 1260 Leu Ala Ser Pro Ala Ser Asn Gly Leu Ala Ser Pro Leu Glu Pro His 1265 1270 1275 1280 Glu Pro His Glu Ile Leu Glu Ala Leu Ala Ala Ser Pro Leu Tyr Ser 1285 1290 1295 Ala Ser Asn Ser Glu Arg Pro His Glu Ser Glu Arg Ala Ser Pro Ala 1300 1305 1310 Ser Pro Leu Glu Ser Glu Arg Leu Tyr Ser Ala Ser Asn Gly Leu Ala 1315 1320 1325 Arg Gly Ile Leu Glu Gly Leu Thr Tyr Arg Ala Ser Asn Thr His Arg 1330 1335 1340 Gly Leu Asn Ser Glu Arg Ala Ser Asn Thr Tyr Arg Ile Leu Glu Gly 1345 1350 1355 1360 Leu Ala Ser Asn Ala Ser Pro Pro His Glu Pro Arg Ile Leu Glu Ala 1365 1370 1375 Ser Asn Gly Leu Leu Glu Ile Leu Glu Leu Glu Ala Ser Pro Thr His 1380 1385 1390 Arg Ala Ser Pro Leu Glu Ile Leu Glu Ser Glu Arg Leu Tyr Ser Ile 1395 1400 1405 Leu Glu Gly Leu Leu Glu Pro Arg Ser Glu Arg Gly Leu Ala Ser Asn 1410 1415 1420 Thr His Arg Gly Leu Ser Glu Arg Leu Glu Thr His Arg Ala Ser Pro 1425 1430 1435 1440 Pro His Glu Ala Ser Asn Val Ala Leu Ala Ser Pro Val Ala Leu Pro 1445 1450 1455 Arg Val Ala Leu Thr Tyr Arg Gly Leu Leu Tyr Ser Gly Leu Asn Pro 1460 1465 1470 Arg Ala Leu Ala Ile Leu Glu Leu Tyr Ser Leu Tyr Ser Ile Leu Glu 1475 1480 1485 Pro His Glu Thr His Arg Ala Ser Pro Gly Leu Ala Ser Asn Thr His 1490 1495 1500 Arg Ile Leu Glu Pro His Glu Gly Leu Asn Thr Tyr Arg Leu Glu Thr 1505 1510 1515 1520 Tyr Arg Ser Glu Arg Gly Leu Asn Thr His Arg Pro His Glu Pro Arg 1525 1530 1535 Leu Glu Ala Ser Pro Ile Leu Glu Ala Arg Gly Ala Ser Pro Ile Leu 1540 1545 1550 Glu Ser Glu Arg Leu Glu Thr His Arg Ser Glu Arg Ser Glu Arg Pro 1555 1560 1565 His Glu Ala Ser Pro Ala Ser Pro Ala Leu Ala Leu Glu Leu Glu Pro 1570 1575 1580 His Glu Ser Glu Arg Ala Ser Asn Leu Tyr Ser Val Ala Leu Thr Tyr 1585 1590 1595 1600 Arg Ser Glu Arg Pro His Glu Pro His Glu Ser Glu Arg Met Glu Thr 1605 1610 1615 Ala Ser Pro Thr Tyr Arg Ile Leu Glu Leu Tyr Ser Thr His Arg Ala 1620 1625 1630 Leu Ala Ala Ser Asn Leu Tyr Ser Val Ala Leu Val Ala Leu Gly Leu 1635 1640 1645 Ala Leu Ala Gly Leu Tyr Leu Glu Pro His Glu Ala Leu Ala Gly Leu 1650 1655 1660 Tyr Thr Arg Pro Val Ala Leu Leu Tyr Ser Gly Leu Asn Ile Leu Glu 1665 1670 1675 1680 Val Ala Leu Ala Ser Asn Ala Ser Pro Pro His Glu Val Ala Leu Ile 1685 1690 1695 Leu Glu Gly Leu Ala Leu Ala Ala Ser Asn Leu Tyr Ser Ser Glu Arg 1700 1705 1710 Ala Ser Asn Thr His Arg Met Glu Thr Ala Ser Pro Leu Tyr Ser Ile 1715 1720 1725 Leu Glu Ala Leu Ala Ala Ser Pro Ile Leu Glu Ser Glu Arg Leu Glu 1730 1735 1740 Ile Leu Glu Val Ala Leu Pro Arg Thr Tyr Arg Ile Leu Glu Gly Leu 1745 1750 1755 1760 Tyr Leu Glu Ala Leu Ala Leu Glu Ala Ser Asn Val Ala Leu Gly Leu 1765 1770 1775 Tyr Ala Ser Asn Gly Leu Thr His Arg Ala Leu Ala Leu Tyr Ser Gly 1780 1785 1790 Leu Tyr Ala Ser Asn Pro His Glu Gly Leu Ala Ser Asn Ala Leu Ala 1795 1800 1805 Pro His Glu Gly Leu Ile Leu Glu Ala Leu Ala Gly Leu Tyr Ala Leu 1810 1815 1820 Ala Ser Glu Arg Ile Leu Glu Leu Glu Leu Glu Gly Leu Pro His Glu 1825 1830 1835 1840 Ile Leu Glu Pro Arg Gly Leu Leu Glu Leu Glu Ile Leu Glu Pro Arg 1845 1850 1855 Val Ala Leu Val Ala Leu Gly Leu Tyr Ala Leu Ala Pro His Glu Leu 1860 1865 1870 Glu Leu Glu Gly Leu Ser Glu Arg Thr Tyr Arg Ile Leu Glu Ala Ser 1875 1880 1885 Pro Ala Ser Asn Leu Tyr Ser Ala Ser Asn Leu Tyr Ser Ile Leu Glu 1890 1895 1900 Ile Leu Glu Leu Tyr Ser Thr His Arg Ile Leu Glu Ala Ser Pro Ala 1905 1910 1915 1920 Ser Asn Ala Leu Ala Leu Glu Thr His Arg Leu Tyr Ser Ala Arg Gly 1925 1930 1935 Ala Ser Asn Gly Leu Leu Tyr Ser Thr Arg Pro Ser Glu Arg Ala Ser 1940 1945 1950 Pro Met Glu Thr Thr Tyr Arg Gly Leu Tyr Leu Glu Ile Leu Glu Val 1955 1960 1965 Ala Leu Ala Leu Ala Gly Leu Asn Thr Arg Pro Leu Glu Ser Glu Arg 1970 1975 1980 Thr His Arg Val Ala Leu Ala Ser Asn Thr His Arg Gly Leu Asn Pro 1985 1990 1995 2000 His Glu Thr Tyr Arg Thr His Arg Ile Leu Glu Leu Tyr Ser Gly Leu 2005 2010 2015 Gly Leu Tyr Met Glu Thr Thr Tyr Arg Leu Tyr Ser Ala Leu Ala Leu 2020 2025 2030 Glu Ala Ser Asn Thr Tyr Arg Gly Leu Asn Ala Leu Ala Gly Leu Asn 2035 2040 2045 Ala Leu Ala Leu Glu Gly Leu Gly Leu Ile Leu Glu Ile Leu Glu Leu 2050 2055 2060 Tyr Ser Thr Tyr Arg Ala Arg Gly Thr Tyr Arg Ala Ser Asn Ile Leu 2065 2070 2075 2080 Glu Thr Tyr Arg Ser Glu Arg Gly Leu Leu Tyr Ser Gly Leu Leu Tyr 2085 2090 2095 Ser Ser Glu Arg Ala Ser Asn Ile Leu Glu Ala Ser Asn Ile Leu Glu 2100 2105 2110 Ala Ser Pro Pro His Glu Ala Ser Asn Ala Ser Pro Ile Leu Glu Ala 2115 2120 2125 Ser Asn Ser Glu Arg Leu Tyr Ser Leu Glu Ala Ser Asn Gly Leu Gly 2130 2135 2140 Leu Tyr Ile Leu Glu Ala Ser Asn Gly Leu Asn Ala Leu Ala Ile Leu 2145 2150 2155 2160 Glu Ala Ser Pro Ala Ser Asn Ile Leu Glu Ala Ser Asn Ala Ser Asn 2165 2170 2175 Pro His Glu Ile Leu Glu Ala Ser Asn Gly Leu Tyr Cys Tyr Ser Ser 2180 2185 2190 Glu Arg Val Ala Leu Ser Glu Arg Thr Tyr Arg Leu Glu Met Glu Thr 2195 2200 2205 Leu Tyr Ser Leu Tyr Ser Met Glu Thr Ile Leu Glu Pro Arg Leu Glu 2210 2215 2220 Ala Leu Ala Val Ala Leu Gly Leu Leu Tyr Ser Leu Glu Leu Glu Ala 2225 2230 2235 2240 Ser Pro Pro His Glu Ala Ser Pro Ala Ser Asn Thr His Arg Leu Glu 2245 2250 2255 Leu Tyr Ser Leu Tyr Ser Ala Ser Asn Leu Glu Leu Glu Ala Ser Asn 2260 2265 2270 Thr Tyr Arg Ile Leu Glu Ala Ser Pro Gly Leu Ala Ser Asn Leu Tyr 2275 2280 2285 Ser Leu Glu Thr Tyr Arg Leu Glu Ile Leu Glu Gly Leu Tyr Ser Glu 2290 2295 2300 Arg Ala Leu Ala Gly Leu Thr Tyr Arg Gly Leu Leu Tyr Ser Ser Glu 2305 2310 2315 2320 Arg Leu Tyr Ser Val Ala Leu Ala Ser Asn Leu Tyr Ser Thr Tyr Arg 2325 2330 2335 Leu Glu Leu Tyr Ser Thr His Arg Ile Leu Glu Met Glu Thr Pro Arg 2340 2345 2350 Pro His Glu Ala Ser Pro Leu Glu Ser Glu Arg Ile Leu Glu Thr Tyr 2355 2360 2365 Arg Thr His Arg Ala Ser Asn Ala Ser Pro Thr His Arg Ile Leu Glu 2370 2375 2380 Leu Glu Ile Leu Glu Gly Leu Met Glu Thr Pro His Glu Ala Ser Asn 2385 2390 2395 2400 Leu Tyr Ser Thr Tyr Arg Ala Ser Asn Ser Glu Arg Gly Leu Ile Leu 2405 2410 2415 Glu Leu Glu Ala Ser Asn Ala Ser Asn Ile Leu Glu Ile Leu Glu Leu 2420 2425 2430 Glu Ala Ser Asn Leu Glu Ala Arg Gly Thr Tyr Arg Leu Tyr Ser Ala 2435 2440 2445 Ser Pro Ala Ser Asn Ala Ser Asn Leu Glu Ile Leu Glu Ala Ser Pro 2450 2455 2460 Leu Glu Ser Glu Arg Gly Leu Tyr Thr Tyr Arg Gly Leu Tyr Ala Leu 2465 2470 2475 2480 Ala Leu Tyr Ser Val Ala Leu Gly Leu Val Ala Leu Thr Tyr Arg Ala 2485 2490 2495 Ser Pro Gly Leu Tyr Val Ala Leu Gly Leu Leu Glu Ala Ser Asn Ala 2500 2505 2510 Ser Pro Leu Tyr Ser Ala Ser Asn Gly Leu Asn Pro His Glu Leu Tyr 2515 2520 2525 Ser Leu Glu Thr His Arg Ser Glu Arg Ser Glu Arg Ala Leu Ala Ala 2530 2535 2540 Ser Asn Ser Glu Arg Leu Tyr Ser Ile Leu Glu Ala Arg Gly Val Ala 2545 2550 2555 2560 Leu Thr His Arg Gly Leu Asn Ala Ser Asn Gly Leu Asn Ala Ser Asn 2565 2570 2575 Ile Leu Glu Ile Leu Glu Pro His Glu Ala Ser Asn Ser Glu Arg Val 2580 2585 2590 Ala Leu Pro His Glu Leu Glu Ala Ser Pro Pro His Glu Ser Glu Arg 2595 2600 2605 Val Ala Leu Ser Glu Arg Pro His Glu Thr Arg Pro Ile Leu Glu Ala 2610 2615 2620 Arg Gly Ile Leu Glu Pro Arg Leu Tyr Ser Thr Tyr Arg Leu Tyr Ser 2625 2630 2635 2640 Ala Ser Asn Ala Ser Pro Gly Leu Tyr Ile Leu Glu Gly Leu Asn Ala 2645 2650 2655 Ser Asn Thr Tyr Arg Ile Leu Glu His Ile Ser Ala Ser Asn Gly Leu 2660 2665 2670 Thr Tyr Arg Thr His Arg Ile Leu Glu Ile Leu Glu Ala Ser Asn Cys 2675 2680 2685 Tyr Ser Met Glu Thr Leu Tyr Ser Ala Ser Asn Ala Ser Asn Ser Glu 2690 2695 2700 Arg Gly Leu Tyr Thr Arg Pro Leu Tyr Ser Ile Leu Glu Ser Glu Arg 2705 2710 2715 2720 Ile Leu Glu Ala Arg Gly Gly Leu Tyr Ala Ser Asn Ala Arg Gly Ile 2725 2730 2735 Leu Glu Ile Leu Glu Thr Arg Pro Thr His Arg Leu Glu Ile Leu Glu 2740 2745 2750 Ala Ser Pro Ile Leu Glu Ala Ser Asn Gly Leu Tyr Leu Tyr Ser Thr 2755 2760 2765 His Arg Leu Tyr Ser Ser Glu Arg Val Ala Leu Pro His Glu Pro His 2770 2775 2780 Glu Gly Leu Thr Tyr Arg Ala Ser Asn Ile Leu Glu Ala Arg Gly Gly 2785 2790 2795 2800 Leu Ala Ser Pro Ile Leu Glu Ser Glu Arg Gly Leu Thr Tyr Arg Ile 2805 2810 2815 Leu Glu Ala Ser Asn Ala Arg Gly Thr Arg Pro Pro His Glu Pro His 2820 2825 2830 Glu Val Ala Leu Thr His Arg Ile Leu Glu Thr His Arg Ala Ser Asn 2835 2840 2845 Ala Ser Asn Leu Glu Ala Ser Asn Ala Ser Asn Ala Leu Ala Leu Tyr 2850 2855 2860 Ser Ile Leu Glu Thr Tyr Arg Ile Leu Glu Ala Ser Asn Gly Leu Tyr 2865 2870 2875 2880 Leu Tyr Ser Leu Glu Gly Leu Ser Glu Arg Ala Ser Asn Thr His Arg 2885 2890 2895 Ala Ser Pro Ile Leu Glu Leu Tyr Ser Ala Ser Pro Ile Leu Glu Ala 2900 2905 2910 Arg Gly Gly Leu Val Ala Leu Ile Leu Glu Ala Leu Ala Ala Ser Asn 2915 2920 2925 Gly Leu Tyr Gly Leu Ile Leu Glu Ile Leu Glu Pro His Glu Leu Tyr 2930 2935 2940 Ser Leu Glu Ala Ser Pro Gly Leu Tyr Ala Ser Pro Ile Leu Glu Ala 2945 2950 2955 2960 Ser Pro Ala Arg Gly Thr His Arg Gly Leu Asn Pro His Glu Ile Leu 2965 2970 2975 Glu Thr Arg Pro Met Glu Thr Leu Tyr Ser Thr Tyr Arg Pro His Glu 2980 2985 2990 Ser Glu Arg Ile Leu Glu Pro His Glu Ala Ser Asn Thr His Arg Gly 2995 3000 3005 Leu Leu Glu Ser Glu Arg Gly Leu Asn Ser Glu Arg Ala Ser Asn Ile 3010 3015 3020 Leu Glu Gly Leu Gly Leu Ala Arg Gly Thr Tyr Arg Leu Tyr Ser Ile 3025 3030 3035 3040 Leu Glu Gly Leu Asn Ser Glu Arg Thr Tyr Arg Ser Glu Arg Gly Leu 3045 3050 3055 Thr Tyr Arg Leu Glu Leu Tyr Ser Ala Ser Pro Pro His Glu Thr Arg 3060 3065 3070 Pro Gly Leu Tyr Ala Ser Asn Pro Arg Leu Glu Met Glu Thr Thr Tyr 3075 3080 3085 Arg Ala Ser Asn Leu Tyr Ser Gly Leu Thr Tyr Arg Thr Tyr Arg Met 3090 3095 3100 Glu Thr Pro His Glu Ala Ser Asn Ala Leu Ala Gly Leu Tyr Ala Ser 3105 3110 3115 3120 Asn Leu Tyr Ser Ala Ser Asn Ser Glu Arg Thr Tyr Arg Ile Leu Glu 3125 3130 3135 Leu Tyr Ser Leu Glu Leu Tyr Ser Leu Tyr Ser Ala Ser Pro Ser Glu 3140 3145 3150 Arg Pro Arg Val Ala Leu Gly Leu Tyr Gly Leu Ile Leu Glu Leu Glu 3155 3160 3165 Thr His Arg Ala Arg Gly Ser Glu Arg Leu Tyr Ser Thr Tyr Arg Ala 3170 3175 3180 Ser Asn Gly Leu Asn Ala Ser Asn Ser Glu Arg Leu Tyr Ser Thr Tyr 3185 3190 3195 3200 Arg Ile Leu Glu Ala Ser Asn Thr Tyr Arg Ala Arg Gly Ala Ser Pro 3205 3210 3215 Leu Glu Thr Tyr Arg Ile Leu Glu Gly Leu Tyr Gly Leu Leu Tyr Ser 3220 3225 3230 Pro His Glu Ile Leu Glu Ile Leu Glu Ala Arg Gly Ala Arg Gly Leu 3235 3240 3245 Tyr Ser Ser Glu Arg Ala Ser Asn Ser Glu Arg Gly Leu Asn Ser Glu 3250 3255 3260 Arg Ile Leu Glu Ala Ser Asn Ala Ser Pro Ala Ser Pro Ile Leu Glu 3265 3270 3275 3280 Val Ala Leu Ala Arg Gly Leu Tyr Ser Gly Leu Ala Ser Pro Thr Tyr 3285 3290 3295 Arg Ile Leu Glu Thr Tyr Arg Leu Glu Ala Ser Pro Pro His Glu Pro 3300 3305 3310 His Glu Ala Ser Asn Leu Glu Ala Ser Asn Gly Leu Asn Gly Leu Thr 3315 3320 3325 Arg Pro Ala Arg Gly Val Ala Leu Thr Tyr Arg Thr His Arg Thr Tyr 3330 3335 3340 Arg Leu Tyr Ser Thr Tyr Arg Pro His Glu Leu Tyr Ser Leu Tyr Ser 3345 3350 3355 3360 Gly Leu Gly Leu Gly Leu Leu Tyr Ser Leu Glu Pro His Glu Leu Glu 3365 3370 3375 Ala Leu Ala Pro Arg Ile Leu Glu Ser Glu Arg Ala Ser Pro Ser Glu 3380 3385 3390 Arg Ala Ser Pro Gly Leu Pro His Glu Thr Tyr Arg Ala Ser Asn Thr 3395 3400 3405 His Arg Ile Leu Glu Gly Leu Asn Ile Leu Glu Leu Tyr Ser Gly Leu 3410 3415 3420 Thr Tyr Arg Ala Ser Pro Gly Leu Gly Leu Asn Pro Arg Thr His Arg 3425 3430 3435 3440 Thr Tyr Arg Ser Glu Arg Cys Tyr Ser Gly Leu Asn Leu Glu Leu Glu 3445 3450 3455 Pro His Glu Leu Tyr Ser Leu Tyr Ser Ala Ser Pro Gly Leu Gly Leu 3460 3465 3470 Ser Glu Arg Thr His Arg Ala Ser Pro Gly Leu Ile Leu Glu Gly Leu 3475 3480 3485 Tyr Leu Glu Ile Leu Glu Gly Leu Tyr Ile Leu Glu His Ile Ser Ala 3490 3495 3500 Arg Gly Pro His Glu Thr Tyr Arg Gly Leu Ser Glu Arg Gly Leu Tyr 3505 3510 3515 3520 Ile Leu Glu Val Ala Leu Pro His Glu Gly Leu Gly Leu Thr Tyr Arg 3525 3530 3535 Leu Tyr Ser Ala Ser Pro Thr Tyr Arg Pro His Glu Cys Tyr Ser Ile 3540 3545 3550 Leu Glu Ser Glu Arg Leu Tyr Ser Thr Arg Pro Thr Tyr Arg Leu Glu 3555 3560 3565 Leu Tyr Ser Gly Leu Val Ala Leu Leu Tyr Ser Ala Arg Gly Leu Tyr 3570 3575 3580 Ser Pro Arg Thr Tyr Arg Ala Ser Asn Leu Glu Leu Tyr Ser Leu Glu 3585 3590 3595 3600 Gly Leu Tyr Cys Tyr Ser Ala Ser Asn Thr Arg Pro Gly Leu Asn Pro 3605 3610 3615 His Glu Ile Leu Glu Pro Arg Leu Tyr Ser Ala Ser Pro Gly Leu Gly 3620 3625 3630 Leu Tyr Thr Arg Pro Thr His Arg Gly Leu 3635 3640 <210> 5 <211> 3843 <212> DNA <213> Clostridium botulinum <400> 5 atgccaataa caattaacaa ctttaattat tcagatcctg ttgataataa aaatatttta 60 tatttagata ctcatttaaa tacattagct aatgagcctg aaaaagcctt tcgcattata 120 gggaatatat gggtaatacc cgatagattt tcaagagatt ctaatccaaa tttaaataaa 180 cctcctcgag ttacaagccc taaaagtggt tattatgatc ctaattattt gagtactgat 240 tctgaaaaag atacattttt aaaagaaatt ataaagttat ttaaaagaat taactctaga 300 gaaataggag aagaattaat atatagactt gcaacagaca taccctttcc tgggaataac 360 aatactccaa ttaatacttt tgattttgat gtagatttta acagtgttga tgttaaaact 420 agacaaggta acaactgggt taaaactggt agtataaatc ctagtgttat aataactgga 480 cctagagaaa acattataga cccagaaact tctacgttta aattaactaa caatactttt 540 gcggcacaag aaggatttgg tgctttatca ataatttcaa tatcacctag atttatgcta 600 acatatagta atgcaactaa taatgtagga gagggtagat tttctaagtc tgaattttgc 660 atggatccaa tactaatttt aatgcatgaa cttaatcatg caatgcataa tttatatgga 720 atagctatac caaatgatca aagaatttca tctgtaacta gtaatatttt ttattctcaa 780 tataaggtga aattagagta tgcagaaata tatgcatttg gaggtccaac tatagacctt 840 attcctaaaa gtgcaaggaa atattttgag gaaaaggcat tggattatta tagatccata 900 gctaaaagac ttaatagtat aactactgca aatccttcaa gctttaataa atatatagga 960 gaatataaac agaaacttat tagaaagtat agattcgtag tagaatcttc aggtgaagtt 1020 gcagtagatc gtaataagtt tgctgagtta tataaagaac ttacacaaat atttacagaa 1080 tttaactacg ctaaaatata taatgtacaa aataggaaaa tatatctttc aaatgtatat 1140 actccggtta cggcaaatat attagacgat aatgtttatg atatacaaaa tggatttaac 1200 atacctaaaa gtaatttaaa tgtactattt atgggtcaaa atttatctcg aaatccagca 1260 ttaagaaaag tcaatcctga aaatatgctt tatttattta caaaattttg ccataaagca 1320 atagatggta gatcattata taataaaaca ttagattgta gagagctttt agttaaaaat 1380 actgacttac cctttatagg tgatattagt gatatcaaaa ctgatatatt tttaagcaaa 1440 gatattaatg aagaaactga agttatagac tatccggaca atgtttcagt ggatcaagtt 1500 attctcagta agaatacctc agaacatgga caactagatt tattataccc tattattgaa 1560 ggtgagagtc aagtattacc gggagagaat caagtctttt atgataatag aactcaaaat 1620 gttgattatt tgaattctta ttattaccta gaatctcaaa aactaagtga taatgttgaa 1680 gattttactt ttacgacatc aattgaggaa gctttggata atagtggaaa agtatatact 1740 tactttccta aactagctga taaagtaaat acgggtgttc aaggtggttt atttttaatg 1800 tgggcaaatg atgtagttga agattttact acaaatattc taagaaaaga tacattagat 1860 aaaatatcag atgtatcagc tattattccc tatataggac ctgcattaaa tataagtaat 1920 tctgtaagaa ggggaaattt tactgaagca tttgcagtta ccggtgtaac tattttatta 1980 gaagcgtttc aagaatttac aatacctgca cttggtgcat ttgtgattta tagtaaggtt 2040 caagaaagaa acgagattat taaaactata gataattgtt tagaacaaag gattaaaaga 2100 tggaaagatt catatgaatg gatgatagga acgtggttat ccaggattac tactcaattt 2160 aataatataa gttatcaaat gtatgattct ttaaattatc aggcagatgc aatcaaagat 2220 aaaatagatt tagaatataa aaaatactca ggaagtgata aagaaaatat aaaaagtcaa 2280 gttgaaaatt taaaaaatag tttagatata aaaatctcgg aagcaatgaa taatataaat 2340 aaatttatac gagaatgttc tgtaacatac ttatttaaaa atatgctccc taaagtaatt 2400 gatgaattaa ataagtttga tttaaaaact aaaacagaat taattaatct tatagatagt 2460 cataatatta ttctagttgg tgaagtagat agattaaaag caaaagtaaa tgagagtttt 2520 gaaaatacaa taccctttaa tattttttca tatactaata attctttatt aaaagatata 2580 attaatgaat atttcaatag tattaatgat tcaaaaattt tgagcttaca aaacaaaaaa 2640 aatgctttag tggatacatc aggatataat gcagaagtga ggctagaagg tgatgttcaa 2700 gttaatacga tatatacaaa tgattttaaa ttaagtagtt caggagataa aattatagta 2760 aatttaaata ataatatttt atatagcgct atttatgaga actctagtgt tagtttttgg 2820 attaagatat ctaaagattt aactaattct cataatgaat atacaataat taatagtata 2880 aaacaaaatt ctgggtggaa attatgtatt aggaatggca atatagaatg gattttacaa 2940 gatattaata gaaagtataa aagtttaatt tttgattata gtgaatcatt aagtcataca 3000 ggatatacaa ataaatggtt ttttgttact ataactaata atataatggg gtatatgaaa 3060 ctttatataa atggagaatt aaagcagagt gaaagaattg aagatttaaa tgaggttaag 3120 ttagataaaa ccatagtatt tggaatagat gagaatatag atgagaatca gatgctttgg 3180 attagagatt ttaatatttt ttctaaagaa ttaagcaatg aagatattaa tattgtatat 3240 gagggacaaa tattaagaaa tgttattaaa gattattggg gaaatccttt gaagtttgat 3300 acagaatatt atattattaa tgataattat atagataggt atatagcacc taaaagtaat 3360 atacttgtac ttgttcagta tccagataga tctaaattat atactggaaa tcctattact 3420 attaaatcag tatctgataa gaatccttat agtagaattt taaatggaga taatataatg 3480 tttcatatgt tatataatag tgggaaatat atgataataa gagatactga tacaatatat 3540 gcaatagaag gaagagagtg ttcaaaaaat tgtgtatatg cattaaaatt acagagtaat 3600 ttaggtaatt atggtatagg tatatttagt ataaaaaata ttgtatctca aaataaatat 3660 tgtagtcaaa ttttctctag ttttatgaaa aatacaatgc ttctagcaga tatatataaa 3720 ccttggagat tttcttttga aaatgcatac acgccagttg cagtaactaa ttatgagaca 3780 aaactattat caacttcatc tttttggaaa tttatttcta gggatccagg atgggtagag 3840 taa 3843 <210> 6 <211> 3617 <212> PRT <213> Clostridium botulinum <400> 6 Met Glu Thr Pro Arg Ile Leu Glu Thr His Arg Ile Leu Glu Ala Ser 1 5 10 15 Asn Ala Ser Asn Pro His Glu Ala Ser Asn Thr Tyr Arg Ser Glu Arg 20 25 30 Ala Ser Pro Pro Arg Val Ala Leu Ala Ser Pro Ala Ser Asn Leu Tyr 35 40 45 Ser Ala Ser Asn Ile Leu Glu Leu Glu Thr Tyr Arg Leu Glu Ala Ser 50 55 60 Pro Thr His Arg His Ile Ser Leu Glu Ala Ser Asn Thr His Arg Leu 65 70 75 80 Glu Ala Leu Ala Ala Ser Asn Gly Leu Pro Arg Gly Leu Leu Tyr Ser 85 90 95 Ala Leu Ala Pro His Glu Ala Arg Gly Ile Leu Glu Ile Leu Glu Gly 100 105 110 Leu Tyr Ala Ser Asn Ile Leu Glu Thr Arg Pro Val Ala Leu Ile Leu 115 120 125 Glu Pro Arg Ala Ser Pro Ala Arg Gly Pro His Glu Ser Glu Arg Ala 130 135 140 Arg Gly Ala Ser Pro Ser Glu Arg Ala Ser Asn Pro Arg Ala Ser Asn 145 150 155 160 Leu Glu Ala Ser Asn Leu Tyr Ser Pro Arg Pro Arg Ala Arg Gly Val 165 170 175 Ala Leu Thr His Arg Ser Glu Arg Pro Arg Leu Tyr Ser Ser Glu Arg 180 185 190 Gly Leu Tyr Thr Tyr Arg Thr Tyr Arg Ala Ser Pro Pro Arg Ala Ser 195 200 205 Asn Thr Tyr Arg Leu Glu Ser Glu Arg Thr His Arg Ala Ser Pro Ser 210 215 220 Glu Arg Gly Leu Leu Tyr Ser Ala Ser Pro Thr His Arg Pro His Glu 225 230 235 240 Leu Glu Leu Tyr Ser Gly Leu Ile Leu Glu Ile Leu Glu Leu Tyr Ser 245 250 255 Leu Glu Pro His Glu Leu Tyr Ser Ala Arg Gly Ile Leu Glu Ala Ser 260 265 270 Asn Ser Glu Arg Ala Arg Gly Gly Leu Ile Leu Glu Gly Leu Tyr Gly 275 280 285 Leu Gly Leu Leu Glu Ile Leu Glu Thr Tyr Arg Ala Arg Gly Leu Glu 290 295 300 Ala Leu Ala Thr His Arg Ala Ser Pro Ile Leu Glu Pro Arg Pro His 305 310 315 320 Glu Pro Arg Gly Leu Tyr Ala Ser Asn Ala Ser Asn Ala Ser Asn Thr 325 330 335 His Arg Pro Arg Ile Leu Glu Ala Ser Asn Thr His Arg Pro His Glu 340 345 350 Ala Ser Pro Pro His Glu Ala Ser Pro Val Ala Leu Ala Ser Pro Pro 355 360 365 His Glu Ala Ser Asn Ser Glu Arg Val Ala Leu Ala Ser Pro Val Ala 370 375 380 Leu Leu Tyr Ser Thr His Arg Ala Arg Gly Gly Leu Asn Gly Leu Tyr 385 390 395 400 Ala Ser Asn Ala Ser Asn Thr Arg Pro Val Ala Leu Leu Tyr Ser Thr 405 410 415 His Arg Gly Leu Tyr Ser Glu Arg Ile Leu Glu Ala Ser Asn Pro Arg 420 425 430 Ser Glu Arg Val Ala Leu Ile Leu Glu Ile Leu Glu Thr His Arg Gly 435 440 445 Leu Tyr Pro Arg Ala Arg Gly Gly Leu Ala Ser Asn Ile Leu Glu Ile 450 455 460 Leu Glu Ala Ser Pro Pro Arg Gly Leu Thr His Arg Ser Glu Arg Thr 465 470 475 480 His Arg Pro His Glu Leu Tyr Ser Leu Glu Thr His Arg Ala Ser Asn 485 490 495 Ala Ser Asn Thr His Arg Pro His Glu Ala Leu Ala Ala Leu Ala Gly 500 505 510 Leu Asn Gly Leu Gly Leu Tyr Pro His Glu Gly Leu Tyr Ala Leu Ala 515 520 525 Leu Glu Ser Glu Arg Ile Leu Glu Ile Leu Glu Ser Glu Arg Ile Leu 530 535 540 Glu Ser Glu Arg Pro Arg Ala Arg Gly Pro His Glu Met Glu Thr Leu 545 550 555 560 Glu Thr His Arg Thr Tyr Arg Ser Glu Arg Ala Ser Asn Ala Leu Ala 565 570 575 Thr His Arg Ala Ser Asn Ala Ser Asn Val Ala Leu Gly Leu Tyr Gly 580 585 590 Leu Gly Leu Tyr Ala Arg Gly Pro His Glu Ser Glu Arg Leu Tyr Ser 595 600 605 Ser Glu Arg Gly Leu Pro His Glu Cys Tyr Ser Met Glu Thr Ala Ser 610 615 620 Pro Pro Arg Ile Leu Glu Leu Glu Ile Leu Glu Leu Glu Met Glu Thr 625 630 635 640 His Ile Ser Gly Leu Leu Glu Ala Ser Asn His Ile Ser Ala Leu Ala 645 650 655 Met Glu Thr His Ile Ser Ala Ser Asn Leu Glu Thr Tyr Arg Gly Leu 660 665 670 Tyr Ile Leu Glu Ala Leu Ala Ile Leu Glu Pro Arg Ala Ser Asn Ala 675 680 685 Ser Pro Gly Leu Asn Ala Arg Gly Ile Leu Glu Ser Glu Arg Ser Glu 690 695 700 Arg Val Ala Leu Thr His Arg Ser Glu Arg Ala Ser Asn Ile Leu Glu 705 710 715 720 Pro His Glu Thr Tyr Arg Ser Glu Arg Gly Leu Asn Thr Tyr Arg Leu 725 730 735 Tyr Ser Val Ala Leu Leu Tyr Ser Leu Glu Gly Leu Thr Tyr Arg Ala 740 745 750 Leu Ala Gly Leu Ile Leu Glu Thr Tyr Arg Ala Leu Ala Pro His Glu 755 760 765 Gly Leu Tyr Gly Leu Tyr Pro Arg Thr His Arg Ile Leu Glu Ala Ser 770 775 780 Pro Leu Glu Ile Leu Glu Pro Arg Leu Tyr Ser Ser Glu Arg Ala Leu 785 790 795 800 Ala Ala Arg Gly Leu Tyr Ser Thr Tyr Arg Pro His Glu Gly Leu Gly 805 810 815 Leu Leu Tyr Ser Ala Leu Ala Leu Glu Ala Ser Pro Thr Tyr Arg Thr 820 825 830 Tyr Arg Ala Arg Gly Ser Glu Arg Ile Leu Glu Ala Leu Ala Leu Tyr 835 840 845 Ser Ala Arg Gly Leu Glu Ala Ser Asn Ser Glu Arg Ile Leu Glu Thr 850 855 860 His Arg Thr His Arg Ala Leu Ala Ala Ser Asn Pro Arg Ser Glu Arg 865 870 875 880 Ser Glu Arg Pro His Glu Ala Ser Asn Leu Tyr Ser Thr Tyr Arg Ile 885 890 895 Leu Glu Gly Leu Tyr Gly Leu Thr Tyr Arg Leu Tyr Ser Gly Leu Asn 900 905 910 Leu Tyr Ser Leu Glu Ile Leu Glu Ala Arg Gly Leu Tyr Ser Thr Tyr 915 920 925 Arg Ala Arg Gly Pro His Glu Val Ala Leu Val Ala Leu Gly Leu Ser 930 935 940 Glu Arg Ser Glu Arg Gly Leu Tyr Gly Leu Val Ala Leu Ala Leu Ala 945 950 955 960 Val Ala Leu Ala Ser Pro Ala Arg Gly Ala Ser Asn Leu Tyr Ser Pro 965 970 975 His Glu Ala Leu Ala Gly Leu Leu Glu Thr Tyr Arg Leu Tyr Ser Gly 980 985 990 Leu Leu Glu Thr His Arg Gly Leu Asn Ile Leu Glu Pro His Glu Thr 995 1000 1005 His Arg Gly Leu Pro His Glu Ala Ser Asn Thr Tyr Arg Ala Leu Ala 1010 1015 1020 Leu Tyr Ser Ile Leu Glu Thr Tyr Arg Ala Ser Asn Val Ala Leu Gly 1025 1030 1035 1040 Leu Asn Ala Ser Asn Ala Arg Gly Leu Tyr Ser Ile Leu Glu Thr Tyr 1045 1050 1055 Arg Leu Glu Ser Glu Arg Ala Ser Asn Val Ala Leu Thr Tyr Arg Thr 1060 1065 1070 His Arg Pro Arg Val Ala Leu Thr His Arg Ala Leu Ala Ala Ser Asn 1075 1080 1085 Ile Leu Glu Leu Glu Ala Ser Pro Ala Ser Pro Ala Ser Asn Val Ala 1090 1095 1100 Leu Thr Tyr Arg Ala Ser Pro Ile Leu Glu Gly Leu Asn Ala Ser Asn 1105 1110 1115 1120 Gly Leu Tyr Pro His Glu Ala Ser Asn Ile Leu Glu Pro Arg Leu Tyr 1125 1130 1135 Ser Ser Glu Arg Ala Ser Asn Leu Glu Ala Ser Asn Val Ala Leu Leu 1140 1145 1150 Glu Pro His Glu Met Glu Thr Gly Leu Tyr Gly Leu Asn Ala Ser Asn 1155 1160 1165 Leu Glu Ser Glu Arg Ala Arg Gly Ala Ser Asn Pro Arg Ala Leu Ala 1170 1175 1180 Leu Glu Ala Arg Gly Leu Tyr Ser Val Ala Leu Ala Ser Asn Pro Arg 1185 1190 1195 1200 Gly Leu Ala Ser Asn Met Glu Thr Leu Glu Thr Tyr Arg Leu Glu Pro 1205 1210 1215 His Glu Thr His Arg Leu Tyr Ser Pro His Glu Cys Tyr Ser His Ile 1220 1225 1230 Ser Leu Tyr Ser Ala Leu Ala Ile Leu Glu Ala Ser Pro Gly Leu Tyr 1235 1240 1245 Ala Arg Gly Ser Glu Arg Leu Glu Thr Tyr Arg Ala Ser Asn Leu Tyr 1250 1255 1260 Ser Thr His Arg Leu Glu Ala Ser Pro Cys Tyr Ser Ala Arg Gly Gly 1265 1270 1275 1280 Leu Leu Glu Leu Glu Val Ala Leu Leu Tyr Ser Ala Ser Asn Thr His 1285 1290 1295 Arg Ala Ser Pro Leu Glu Pro Arg Pro His Glu Ile Leu Glu Gly Leu 1300 1305 1310 Tyr Ala Ser Pro Ile Leu Glu Ser Glu Arg Ala Ser Pro Ile Leu Glu 1315 1320 1325 Leu Tyr Ser Thr His Arg Ala Ser Pro Ile Leu Glu Pro His Glu Leu 1330 1335 1340 Glu Ser Glu Arg Leu Tyr Ser Ala Ser Pro Ile Leu Glu Ala Ser Asn 1345 1350 1355 1360 Gly Leu Gly Leu Thr His Arg Gly Leu Val Ala Leu Ile Leu Glu Ala 1365 1370 1375 Ser Pro Thr Tyr Arg Pro Arg Ala Ser Pro Ala Ser Asn Val Ala Leu 1380 1385 1390 Ser Glu Arg Val Ala Leu Ala Ser Pro Gly Leu Asn Val Ala Leu Ile 1395 1400 1405 Leu Glu Leu Glu Ser Glu Arg Leu Tyr Ser Ala Ser Asn Thr His Arg 1410 1415 1420 Ser Glu Arg Gly Leu His Ile Ser Gly Leu Tyr Gly Leu Asn Leu Glu 1425 1430 1435 1440 Ala Ser Pro Leu Glu Leu Glu Thr Tyr Arg Pro Arg Ile Leu Glu Ile 1445 1450 1455 Leu Glu Gly Leu Gly Leu Tyr Gly Leu Ser Glu Arg Gly Leu Asn Val 1460 1465 1470 Ala Leu Leu Glu Pro Arg Gly Leu Tyr Gly Leu Ala Ser Asn Gly Leu 1475 1480 1485 Asn Val Ala Leu Pro His Glu Thr Tyr Arg Ala Ser Pro Ala Ser Asn 1490 1495 1500 Ala Arg Gly Thr His Arg Gly Leu Asn Ala Ser Asn Val Ala Leu Ala 1505 1510 1515 1520 Ser Pro Thr Tyr Arg Leu Glu Ala Ser Asn Ser Glu Arg Thr Tyr Arg 1525 1530 1535 Thr Tyr Arg Thr Tyr Arg Leu Glu Gly Leu Ser Glu Arg Gly Leu Asn 1540 1545 1550 Leu Tyr Ser Leu Glu Ser Glu Arg Ala Ser Pro Ala Ser Asn Val Ala 1555 1560 1565 Leu Gly Leu Ala Ser Pro Pro His Glu Thr His Arg Pro His Glu Thr 1570 1575 1580 His Arg Thr His Arg Ser Glu Arg Ile Leu Glu Gly Leu Gly Leu Ala 1585 1590 1595 1600 Leu Ala Leu Glu Ala Ser Pro Ala Ser Asn Ser Glu Arg Gly Leu Tyr 1605 1610 1615 Leu Tyr Ser Val Ala Leu Thr Tyr Arg Thr His Arg Thr Tyr Arg Pro 1620 1625 1630 His Glu Pro Arg Leu Tyr Ser Leu Glu Ala Leu Ala Ala Ser Pro Leu 1635 1640 1645 Tyr Ser Val Ala Leu Ala Ser Asn Thr His Arg Gly Leu Tyr Val Ala 1650 1655 1660 Leu Gly Leu Asn Gly Leu Tyr Gly Leu Tyr Leu Glu Pro His Glu Leu 1665 1670 1675 1680 Glu Met Glu Thr Thr Arg Pro Ala Leu Ala Ala Ser Asn Ala Ser Pro 1685 1690 1695 Val Ala Leu Val Ala Leu Gly Leu Ala Ser Pro Pro His Glu Thr His 1700 1705 1710 Arg Thr His Arg Ala Ser Asn Ile Leu Glu Leu Glu Ala Arg Gly Leu 1715 1720 1725 Tyr Ser Ala Ser Pro Thr His Arg Leu Glu Ala Ser Pro Leu Tyr Ser 1730 1735 1740 Ile Leu Glu Ser Glu Arg Ala Ser Pro Val Ala Leu Ser Glu Arg Ala 1745 1750 1755 1760 Leu Ala Ile Leu Glu Ile Leu Glu Pro Arg Thr Tyr Arg Ile Leu Glu 1765 1770 1775 Gly Leu Tyr Pro Arg Ala Leu Ala Leu Glu Ala Ser Asn Ile Leu Glu 1780 1785 1790 Ser Glu Arg Ala Ser Asn Ser Glu Arg Val Ala Leu Ala Arg Gly Ala 1795 1800 1805 Arg Gly Gly Leu Tyr Ala Ser Asn Pro His Glu Thr His Arg Gly Leu 1810 1815 1820 Ala Leu Ala Pro His Glu Ala Leu Ala Val Ala Leu Thr His Arg Gly 1825 1830 1835 1840 Leu Tyr Val Ala Leu Thr His Arg Ile Leu Glu Leu Glu Leu Glu Gly 1845 1850 1855 Leu Ala Leu Ala Pro His Glu Gly Leu Asn Gly Leu Pro His Glu Thr 1860 1865 1870 His Arg Ile Leu Glu Pro Arg Ala Leu Ala Leu Glu Gly Leu Tyr Ala 1875 1880 1885 Leu Ala Pro His Glu Val Ala Leu Ile Leu Glu Thr Tyr Arg Ser Glu 1890 1895 1900 Arg Leu Tyr Ser Val Ala Leu Gly Leu Asn Gly Leu Ala Arg Gly Ala 1905 1910 1915 1920 Ser Asn Gly Leu Ile Leu Glu Ile Leu Glu Leu Tyr Ser Thr His Arg 1925 1930 1935 Ile Leu Glu Ala Ser Pro Ala Ser Asn Cys Tyr Ser Leu Glu Gly Leu 1940 1945 1950 Gly Leu Asn Ala Arg Gly Ile Leu Glu Leu Tyr Ser Ala Arg Gly Thr 1955 1960 1965 Arg Pro Leu Tyr Ser Ala Ser Pro Ser Glu Arg Thr Tyr Arg Gly Leu 1970 1975 1980 Thr Arg Pro Met Glu Thr Ile Leu Glu Gly Leu Tyr Thr His Arg Thr 1985 1990 1995 2000 Arg Pro Leu Glu Ser Glu Arg Ala Arg Gly Ile Leu Glu Thr His Arg 2005 2010 2015 Thr His Arg Gly Leu Asn Pro His Glu Ala Ser Asn Ala Ser Asn Ile 2020 2025 2030 Leu Glu Ser Glu Arg Thr Tyr Arg Gly Leu Asn Met Glu Thr Thr Tyr 2035 2040 2045 Arg Ala Ser Pro Ser Glu Arg Leu Glu Ala Ser Asn Thr Tyr Arg Gly 2050 2055 2060 Leu Asn Ala Leu Ala Ala Ser Pro Ala Leu Ala Ile Leu Glu Leu Tyr 2065 2070 2075 2080 Ser Ala Ser Pro Leu Tyr Ser Ile Leu Glu Ala Ser Pro Leu Glu Gly 2085 2090 2095 Leu Thr Tyr Arg Leu Tyr Ser Leu Tyr Ser Thr Tyr Arg Ser Glu Arg 2100 2105 2110 Gly Leu Tyr Ser Glu Arg Ala Ser Pro Leu Tyr Ser Gly Leu Ala Ser 2115 2120 2125 Asn Ile Leu Glu Leu Tyr Ser Ser Glu Arg Gly Leu Asn Val Ala Leu 2130 2135 2140 Gly Leu Ala Ser Asn Leu Glu Leu Tyr Ser Ala Ser Asn Ser Glu Arg 2145 2150 2155 2160 Leu Glu Ala Ser Pro Ile Leu Glu Leu Tyr Ser Ile Leu Glu Ser Glu 2165 2170 2175 Arg Gly Leu Ala Leu Ala Met Glu Thr Ala Ser Asn Ala Ser Asn Ile 2180 2185 2190 Leu Glu Ala Ser Asn Leu Tyr Ser Pro His Glu Ile Leu Glu Ala Arg 2195 2200 2205 Gly Gly Leu Cys Tyr Ser Ser Glu Arg Val Ala Leu Thr His Arg Thr 2210 2215 2220 Tyr Arg Leu Glu Pro His Glu Leu Tyr Ser Ala Ser Asn Met Glu Thr 2225 2230 2235 2240 Leu Glu Pro Arg Leu Tyr Ser Val Ala Leu Ile Leu Glu Ala Ser Pro 2245 2250 2255 Gly Leu Leu Glu Ala Ser Asn Leu Tyr Ser Pro His Glu Ala Ser Pro 2260 2265 2270 Leu Glu Leu Tyr Ser Thr His Arg Leu Tyr Ser Thr His Arg Gly Leu 2275 2280 2285 Leu Glu Ile Leu Glu Ala Ser Asn Leu Glu Ile Leu Glu Ala Ser Pro 2290 2295 2300 Ser Glu Arg His Ile Ser Ala Ser Asn Ile Leu Glu Ile Leu Glu Leu 2305 2310 2315 2320 Glu Val Ala Leu Gly Leu Tyr Gly Leu Val Ala Leu Ala Ser Pro Ala 2325 2330 2335 Arg Gly Leu Glu Leu Tyr Ser Ala Leu Ala Leu Tyr Ser Val Ala Leu 2340 2345 2350 Ala Ser Asn Gly Leu Ser Glu Arg Pro His Glu Gly Leu Ala Ser Asn 2355 2360 2365 Thr His Arg Ile Leu Glu Pro Arg Pro His Glu Ala Ser Asn Ile Leu 2370 2375 2380 Glu Pro His Glu Ser Glu Arg Thr Tyr Arg Thr His Arg Ala Ser Asn 2385 2390 2395 2400 Ala Ser Asn Ser Glu Arg Leu Glu Leu Glu Leu Tyr Ser Ala Ser Pro 2405 2410 2415 Ile Leu Glu Ile Leu Glu Ala Ser Asn Gly Leu Thr Tyr Arg Pro His 2420 2425 2430 Glu Ala Ser Asn Ser Glu Arg Ile Leu Glu Ala Ser Asn Ala Ser Pro 2435 2440 2445 Ser Glu Arg Leu Tyr Ser Ile Leu Glu Leu Glu Ser Glu Arg Leu Glu 2450 2455 2460 Gly Leu Asn Ala Ser Asn Leu Tyr Ser Leu Tyr Ser Ala Ser Asn Ala 2465 2470 2475 2480 Leu Ala Leu Glu Val Ala Leu Ala Ser Pro Thr His Arg Ser Glu Arg 2485 2490 2495 Gly Leu Tyr Thr Tyr Arg Ala Ser Asn Ala Leu Ala Gly Leu Val Ala 2500 2505 2510 Leu Ala Arg Gly Leu Glu Gly Leu Gly Leu Tyr Ala Ser Pro Val Ala 2515 2520 2525 Leu Gly Leu Asn Val Ala Leu Ala Ser Asn Thr His Arg Ile Leu Glu 2530 2535 2540 Thr Tyr Arg Thr His Arg Ala Ser Asn Ala Ser Pro Pro His Glu Leu 2545 2550 2555 2560 Tyr Ser Leu Glu Ser Glu Arg Ser Glu Arg Ser Glu Arg Gly Leu Tyr 2565 2570 2575 Ala Ser Pro Leu Tyr Ser Ile Leu Glu Ile Leu Glu Val Ala Leu Ala 2580 2585 2590 Ser Asn Leu Glu Ala Ser Asn Ala Ser Asn Ala Ser Asn Ile Leu Glu 2595 2600 2605 Leu Glu Thr Tyr Arg Ser Glu Arg Ala Leu Ala Ile Leu Glu Thr Tyr 2610 2615 2620 Arg Gly Leu Ala Ser Asn Ser Glu Arg Ser Glu Arg Val Ala Leu Ser 2625 2630 2635 2640 Glu Arg Pro His Glu Thr Arg Pro Ile Leu Glu Leu Tyr Ser Ile Leu 2645 2650 2655 Glu Ser Glu Arg Leu Tyr Ser Ala Ser Pro Leu Glu Thr His Arg Ala 2660 2665 2670 Ser Asn Ser Glu Arg His Ile Ser Ala Ser Asn Gly Leu Thr Tyr Arg 2675 2680 2685 Thr His Arg Ile Leu Glu Ile Leu Glu Ala Ser Asn Ser Glu Arg Ile 2690 2695 2700 Leu Glu Leu Tyr Ser Gly Leu Asn Ala Ser Asn Ser Glu Arg Gly Leu 2705 2710 2715 2720 Tyr Thr Arg Pro Leu Tyr Ser Leu Glu Cys Tyr Ser Ile Leu Glu Ala 2725 2730 2735 Arg Gly Ala Ser Asn Gly Leu Tyr Ala Ser Asn Ile Leu Glu Gly Leu 2740 2745 2750 Thr Arg Pro Ile Leu Glu Leu Glu Gly Leu Asn Ala Ser Pro Ile Leu 2755 2760 2765 Glu Ala Ser Asn Ala Arg Gly Leu Tyr Ser Thr Tyr Arg Leu Tyr Ser 2770 2775 2780 Ser Glu Arg Leu Glu Ile Leu Glu Pro His Glu Ala Ser Pro Thr Tyr 2785 2790 2795 2800 Arg Ser Glu Arg Gly Leu Ser Glu Arg Leu Glu Ser Glu Arg His Ile 2805 2810 2815 Ser Thr His Arg Gly Leu Tyr Thr Tyr Arg Thr His Arg Ala Ser Asn 2820 2825 2830 Leu Tyr Ser Thr Arg Pro Pro His Glu Pro His Glu Val Ala Leu Thr 2835 2840 2845 His Arg Ile Leu Glu Thr His Arg Ala Ser Asn Ala Ser Asn Ile Leu 2850 2855 2860 Glu Met Glu Thr Gly Leu Tyr Thr Tyr Arg Met Glu Thr Leu Tyr Ser 2865 2870 2875 2880 Leu Glu Thr Tyr Arg Ile Leu Glu Ala Ser Asn Gly Leu Tyr Gly Leu 2885 2890 2895 Leu Glu Leu Tyr Ser Gly Leu Asn Ser Glu Arg Gly Leu Ala Arg Gly 2900 2905 2910 Ile Leu Glu Gly Leu Ala Ser Pro Leu Glu Ala Ser Asn Gly Leu Val 2915 2920 2925 Ala Leu Leu Tyr Ser Leu Glu Ala Ser Pro Leu Tyr Ser Thr His Arg 2930 2935 2940 Ile Leu Glu Val Ala Leu Pro His Glu Gly Leu Tyr Ile Leu Glu Ala 2945 2950 2955 2960 Ser Pro Gly Leu Ala Ser Asn Ile Leu Glu Ala Ser Pro Gly Leu Ala 2965 2970 2975 Ser Asn Gly Leu Asn Met Glu Thr Leu Glu Thr Arg Pro Ile Leu Glu 2980 2985 2990 Ala Arg Gly Ala Ser Pro Pro His Glu Ala Ser Asn Ile Leu Glu Pro 2995 3000 3005 His Glu Ser Glu Arg Leu Tyr Ser Gly Leu Leu Glu Ser Glu Arg Ala 3010 3015 3020 Ser Asn Gly Leu Ala Ser Pro Ile Leu Glu Ala Ser Asn Ile Leu Glu 3025 3030 3035 3040 Val Ala Leu Thr Tyr Arg Gly Leu Gly Leu Tyr Gly Leu Asn Ile Leu 3045 3050 3055 Glu Leu Glu Ala Arg Gly Ala Ser Asn Val Ala Leu Ile Leu Glu Leu 3060 3065 3070 Tyr Ser Ala Ser Pro Thr Tyr Arg Thr Arg Pro Gly Leu Tyr Ala Ser 3075 3080 3085 Asn Pro Arg Leu Glu Leu Tyr Ser Pro His Glu Ala Ser Pro Thr His 3090 3095 3100 Arg Gly Leu Thr Tyr Arg Thr Tyr Arg Ile Leu Glu Ile Leu Glu Ala 3105 3110 3115 3120 Ser Asn Ala Ser Pro Ala Ser Asn Thr Tyr Arg Ile Leu Glu Ala Ser 3125 3130 3135 Pro Ala Arg Gly Thr Tyr Arg Ile Leu Glu Ala Leu Ala Pro Arg Leu 3140 3145 3150 Tyr Ser Ser Glu Arg Ala Ser Asn Ile Leu Glu Leu Glu Val Ala Leu 3155 3160 3165 Leu Glu Val Ala Leu Gly Leu Asn Thr Tyr Arg Pro Arg Ala Ser Pro 3170 3175 3180 Ala Arg Gly Ser Glu Arg Leu Tyr Ser Leu Glu Thr Tyr Arg Thr His 3185 3190 3195 3200 Arg Gly Leu Tyr Ala Ser Asn Pro Arg Ile Leu Glu Thr His Arg Ile 3205 3210 3215 Leu Glu Leu Tyr Ser Ser Glu Arg Val Ala Leu Ser Glu Arg Ala Ser 3220 3225 3230 Pro Leu Tyr Ser Ala Ser Asn Pro Arg Thr Tyr Arg Ser Glu Arg Ala 3235 3240 3245 Arg Gly Ile Leu Glu Leu Glu Ala Ser Asn Gly Leu Tyr Ala Ser Pro 3250 3255 3260 Ala Ser Asn Ile Leu Glu Met Glu Thr Pro His Glu His Ile Ser Met 3265 3270 3275 3280 Glu Thr Leu Glu Thr Tyr Arg Ala Ser Asn Ser Glu Arg Gly Leu Tyr 3285 3290 3295 Leu Tyr Ser Thr Tyr Arg Met Glu Thr Ile Leu Glu Ile Leu Glu Ala 3300 3305 3310 Arg Gly Ala Ser Pro Thr His Arg Ala Ser Pro Thr His Arg Ile Leu 3315 3320 3325 Glu Thr Tyr Arg Ala Leu Ala Ile Leu Glu Gly Leu Gly Leu Tyr Ala 3330 3335 3340 Arg Gly Gly Leu Cys Tyr Ser Ser Glu Arg Leu Tyr Ser Ala Ser Asn 3345 3350 3355 3360 Cys Tyr Ser Val Ala Leu Thr Tyr Arg Ala Leu Ala Leu Glu Leu Tyr 3365 3370 3375 Ser Leu Glu Gly Leu Asn Ser Glu Arg Ala Ser Asn Leu Glu Gly Leu 3380 3385 3390 Tyr Ala Ser Asn Thr Tyr Arg Gly Leu Tyr Ile Leu Glu Gly Leu Tyr 3395 3400 3405 Ile Leu Glu Pro His Glu Ser Glu Arg Ile Leu Glu Leu Tyr Ser Ala 3410 3415 3420 Ser Asn Ile Leu Glu Val Ala Leu Ser Glu Arg Gly Leu Asn Ala Ser 3425 3430 3435 3440 Asn Leu Tyr Ser Thr Tyr Arg Cys Tyr Ser Ser Glu Arg Gly Leu Asn 3445 3450 3455 Ile Leu Glu Pro His Glu Ser Glu Arg Ser Glu Arg Pro His Glu Met 3460 3465 3470 Glu Thr Leu Tyr Ser Ala Ser Asn Thr His Arg Met Glu Thr Leu Glu 3475 3480 3485 Leu Glu Ala Leu Ala Ala Ser Pro Ile Leu Glu Thr Tyr Arg Leu Tyr 3490 3495 3500 Ser Pro Arg Thr Arg Pro Ala Arg Gly Pro His Glu Ser Glu Arg Pro 3505 3510 3515 3520 His Glu Gly Leu Ala Ser Asn Ala Leu Ala Thr Tyr Arg Thr His Arg 3525 3530 3535 Pro Arg Val Ala Leu Ala Leu Ala Val Ala Leu Thr His Arg Ala Ser 3540 3545 3550 Asn Thr Tyr Arg Gly Leu Thr His Arg Leu Tyr Ser Leu Glu Leu Glu 3555 3560 3565 Ser Glu Arg Thr His Arg Ser Glu Arg Ser Glu Arg Pro His Glu Thr 3570 3575 3580 Arg Pro Leu Tyr Ser Pro His Glu Ile Leu Glu Ser Glu Arg Ala Arg 3585 3590 3595 3600 Gly Ala Ser Pro Pro Arg Gly Leu Tyr Thr Arg Pro Val Ala Leu Gly 3605 3610 3615 Leu <210> 7 <211> 3858 <212> DNA <213> Clostridium botulinum <400> 7 atgacatggc cagtaaaaga ttttaattat agtgatcctg ttaatgacaa tgatatatta 60 tatttaagaa taccacaaaa taagttaatt actacacctg taaaagcttt tatgattact 120 caaaatattt gggtaatacc agaaagattt tcatcagata ctaatccaag tttaagtaaa 180 ccgcctagac ctacttcaaa gtatcaaagt tattatgatc ctagttattt atctactgat 240 gagcaaaaag atacattttt aaaagggatt ataaaattat ttaaaagaat taatgaaaga 300 gatataggaa aaaaattaat aaattattta gtagttggtt caccttttat gggagattca 360 agtacgcctg aagatacatt tgattttaca cgtcatacta ctaatattgc agttgaaaag 420 tttgaaaatg gtagttggaa agtaacaaat attataacac caagtgtatt gatatttgga 480 ccacttccta atatattaga ctatacagca tcccttacat tgcaaggaca acaatcaaat 540 ccatcatttg aagggtttgg aacattatct atactaaaag tagcacctga atttttgtta 600 acatttagtg atgtaacatc taatcaaagt tcagctgtat taggcaaatc tatattttgt 660 atggatccag taatagcttt aatgcatgag ttaacacatt ctttgcatca attgtatgga 720 ataaatatac catctgataa aaggattcgt ccacaagtta gcgagggatt tttttctcaa 780 gatggaccca acgtacaatt tgaggaatta tacacatttg gaggatcaga tgttgaaata 840 atacctcaaa ttgaaagatt acaattaaga gaaaaagcat taggtcacta taaagatata 900 gcgaaaagac ttaataatat taataaaact attccttcta gttggagtag taatatagat 960 aaatataaaa aaatattttc tgaaaagtat aattttgata aagataatac aggaaatttt 1020 gttgtaaata ttgataaatt caatagctta tattcagact tgactaatgt tatgtcagaa 1080 gttgtttatt cttcgcaata taatgttaaa aacaggactc attatttttc aaagcattat 1140 ctacctgtat ttgcaaatat attagatgat aatatttata ctataataaa cggttttaat 1200 ttaacaacta aaggttttaa tatagaaaat tcgggtcaga atatagaaag gaatcctgca 1260 ctacaaaaac ttagttcaga aagtgtagta gatttgttta caaaagtatg tttaagatta 1320 acaagaaata gtagagatga ttcaacatgt attcaagtta aaaataatac attaccttat 1380 gtagctgata aagatagcat ttcacaagaa atatttgaaa gtcaaattat tacagatgag 1440 actaatgtag aaaattattc agataatttt tcattagatg aatctatttt agatgcaaaa 1500 gtccctacta atcctgaagc agtagatcca ctgttaccca atgttaatat ggaaccttta 1560 aatgttccag gtgaagaaga agtattttat gatgatatta ctaaagatgt tgattattta 1620 aactcttatt attatttgga agcccaaaaa ttaagtaata atgttgaaaa tattactctt 1680 acaacttcag ttgaagaagc attaggttat agcaataaga tatacacatt tttacctagc 1740 ttagctgaaa aagtgaataa aggtgttcaa gcaggtttat tcttaaattg ggcgaatgaa 1800 gtagttgagg attttactac aaatattatg aaaaaagata cattggataa aatatcagat 1860 gtatcagcca taattccata tataggacct gccttaaata taggaaattc agcattaagg 1920 ggaaacttta agcaagcatt tgcaacagct ggtgtagctt ttttgttaga aggatttcca 1980 gagtttacaa tacctgcact cggtgtattt accttttata gttctattca agaaagagag 2040 aaaattatta aaactataga aaattgttta gaacaaagag ttaagagatg gaaagattca 2100 tatcaatgga tggtatcaaa ttggttgtca agaattacta ctcgatttaa tcatataagt 2160 tatcaaatgt atgattcttt gagttatcag gcagatgcaa tcaaagctaa aatagattta 2220 gaatataaaa aatactcagg aagtgataaa gaaaatataa aaagtcaagt tgaaaattta 2280 aaaaatagtt tagatgtaaa aatctcggaa gcaatgaata atataaataa atttatacga 2340 gaatgttctg taacatactt atttaaaaat atgctcccta aagtaattga tgaattaaat 2400 aagtttgatt taaaaactaa aacagaatta attaatctta tagatagtca taatattatt 2460 ctagttggtg aagtagatag attaaaagca aaagtaaatg agagttttga aaatacaata 2520 ccctttaata ttttttcata tactaataat tctttattaa aagatatgat taatgaatat 2580 ttcaatagta ttaatgattc aaaaattttg agcttacaaa ataaaaaaaa tactttgatg 2640 gatacatcag gatataacgc agaagtgaga gtagaaggca atgttcagct taatccaata 2700 tttccatttg actttaaatt aggtagttca ggggatgata gaggtaaagt tatagtaacc 2760 cagaatgaaa atattgtata taatgctatg tatgaaagtt ttagtattag tttttggatt 2820 aggataaata aatgggtaag taatttacct ggatatacta taattgatag tgttaaaaat 2880 aactcaggtt ggagtatagg tattattagt aattttttag tgtttacttt aaaacaaaat 2940 gaaaatagtg aacaagatat aaactttagt tatgatatat caaagaatgc tgcgggatat 3000 aataaatggt tttttgtaac tattactacc aatatgatgg gaaatatgat gatttatata 3060 aatggaaaat taatagatac tataaaagtt aaagagttaa ctggaattaa ttttagcaaa 3120 actataacat ttcaaatgaa taaaattcca aatactggct taattacctc agattctgat 3180 aacatcaata tgtggataag ggatttttat atctttgcta aagaattaga tgataaagat 3240 attaatatat tatttaatag cttgcaatat actaatgttg taaaagatta ttggggaaat 3300 gatttaagat atgataaaga atattacatg attaacgtaa attatatgaa tagatatatg 3360 tctaaaaaag gcaatggaat tgtttttaat acacgtaaaa ataataatga cttcaatgaa 3420 ggatataaaa ttataataaa aagaattaga ggaaatacaa atgatactag agtacgagga 3480 gaaaatgtat tatattttaa tactacaatt gataacaaac aatatagttt aggtatgtat 3540 aaaccttcta gaaatctagg gactgattta gttccactag gtgcattgga tcaaccaatg 3600 gatgagatac gtaaatatgg ttcgtttata atacaaccat gcaatacttt tgattactat 3660 gcatcacaat tatttttgtc aagtaatgca acaacaaata ggcttggaat actatcaatt 3720 ggtagttata gtttcaaact tggagatgac tattggttta atcacgaata tttaattcct 3780 gttataaaaa tagagcatta tgcttcatta ttagaatcaa catcaactca ttgggttttt 3840 gtacctgcaa gtgaataa 3858 <210> 8 <211> 3632 <212> PRT <213> Clostridium botulinum <400> 8 Met Glu Thr Thr His Arg Thr Arg Pro Pro Arg Val Ala Leu Leu Tyr 1 5 10 15 Ser Ala Ser Pro Pro His Glu Ala Ser Asn Thr Tyr Arg Ser Glu Arg 20 25 30 Ala Ser Pro Pro Arg Val Ala Leu Ala Ser Asn Ala Ser Pro Ala Ser 35 40 45 Asn Ala Ser Pro Ile Leu Glu Leu Glu Thr Tyr Arg Leu Glu Ala Arg 50 55 60 Gly Ile Leu Glu Pro Arg Gly Leu Asn Ala Ser Asn Leu Tyr Ser Leu 65 70 75 80 Glu Ile Leu Glu Thr His Arg Thr His Arg Pro Arg Val Ala Leu Leu 85 90 95 Tyr Ser Ala Leu Ala Pro His Glu Met Glu Thr Ile Leu Glu Thr His 100 105 110 Arg Gly Leu Asn Ala Ser Asn Ile Leu Glu Thr Arg Pro Val Ala Leu 115 120 125 Ile Leu Glu Pro Arg Gly Leu Ala Arg Gly Pro His Glu Ser Glu Arg 130 135 140 Ser Glu Arg Ala Ser Pro Thr His Arg Ala Ser Asn Pro Arg Ser Glu 145 150 155 160 Arg Leu Glu Ser Glu Arg Leu Tyr Ser Pro Arg Pro Arg Ala Arg Gly 165 170 175 Pro Arg Thr His Arg Ser Glu Arg Leu Tyr Ser Thr Tyr Arg Gly Leu 180 185 190 Asn Ser Glu Arg Thr Tyr Arg Thr Tyr Arg Ala Ser Pro Pro Arg Ser 195 200 205 Glu Arg Thr Tyr Arg Leu Glu Ser Glu Arg Thr His Arg Ala Ser Pro 210 215 220 Gly Leu Gly Leu Asn Leu Tyr Ser Ala Ser Pro Thr His Arg Pro His 225 230 235 240 Glu Leu Glu Leu Tyr Ser Gly Leu Tyr Ile Leu Glu Ile Leu Glu Leu 245 250 255 Tyr Ser Leu Glu Pro His Glu Leu Tyr Ser Ala Arg Gly Ile Leu Glu 260 265 270 Ala Ser Asn Gly Leu Ala Arg Gly Ala Ser Pro Ile Leu Glu Gly Leu 275 280 285 Tyr Leu Tyr Ser Leu Tyr Ser Leu Glu Ile Leu Glu Ala Ser Asn Thr 290 295 300 Tyr Arg Leu Glu Val Ala Leu Val Ala Leu Gly Leu Tyr Ser Glu Arg 305 310 315 320 Pro Arg Pro His Glu Met Glu Thr Gly Leu Tyr Ala Ser Pro Ser Glu 325 330 335 Arg Ser Glu Arg Thr His Arg Pro Arg Gly Leu Ala Ser Pro Thr His 340 345 350 Arg Pro His Glu Ala Ser Pro Pro His Glu Thr His Arg Ala Arg Gly 355 360 365 His Ile Ser Thr His Arg Thr His Arg Ala Ser Asn Ile Leu Glu Ala 370 375 380 Leu Ala Val Ala Leu Gly Leu Leu Tyr Ser Pro His Glu Gly Leu Ala 385 390 395 400 Ser Asn Gly Leu Tyr Ser Glu Arg Thr Arg Pro Leu Tyr Ser Val Ala 405 410 415 Leu Thr His Arg Ala Ser Asn Ile Leu Glu Ile Leu Glu Thr His Arg 420 425 430 Pro Arg Ser Glu Arg Val Ala Leu Leu Glu Ile Leu Glu Pro His Glu 435 440 445 Gly Leu Tyr Pro Arg Leu Glu Pro Arg Ala Ser Asn Ile Leu Glu Leu 450 455 460 Glu Ala Ser Pro Thr Tyr Arg Thr His Arg Ala Leu Ala Ser Glu Arg 465 470 475 480 Leu Glu Thr His Arg Leu Glu Gly Leu Asn Gly Leu Tyr Gly Leu Asn 485 490 495 Gly Leu Asn Ser Glu Arg Ala Ser Asn Pro Arg Ser Glu Arg Pro His 500 505 510 Glu Gly Leu Gly Leu Tyr Pro His Glu Gly Leu Tyr Thr His Arg Leu 515 520 525 Glu Ser Glu Arg Ile Leu Glu Leu Glu Leu Tyr Ser Val Ala Leu Ala 530 535 540 Leu Ala Pro Arg Gly Leu Pro His Glu Leu Glu Leu Glu Thr His Arg 545 550 555 560 Pro His Glu Ser Glu Arg Ala Ser Pro Val Ala Leu Thr His Arg Ser 565 570 575 Glu Arg Ala Ser Asn Gly Leu Asn Ser Glu Arg Ser Glu Arg Ala Leu 580 585 590 Ala Val Ala Leu Leu Glu Gly Leu Tyr Leu Tyr Ser Ser Glu Arg Ile 595 600 605 Leu Glu Pro His Glu Cys Tyr Ser Met Glu Thr Ala Ser Pro Pro Arg 610 615 620 Val Ala Leu Ile Leu Glu Ala Leu Ala Leu Glu Met Glu Thr His Ile 625 630 635 640 Ser Gly Leu Leu Glu Thr His Arg His Ile Ser Ser Glu Arg Leu Glu 645 650 655 His Ile Ser Gly Leu Asn Leu Glu Thr Tyr Arg Gly Leu Tyr Ile Leu 660 665 670 Glu Ala Ser Asn Ile Leu Glu Pro Arg Ser Glu Arg Ala Ser Pro Leu 675 680 685 Tyr Ser Ala Arg Gly Ile Leu Glu Ala Arg Gly Pro Arg Gly Leu Asn 690 695 700 Val Ala Leu Ser Glu Arg Gly Leu Gly Leu Tyr Pro His Glu Pro His 705 710 715 720 Glu Ser Glu Arg Gly Leu Asn Ala Ser Pro Gly Leu Tyr Pro Arg Ala 725 730 735 Ser Asn Val Ala Leu Gly Leu Asn Pro His Glu Gly Leu Gly Leu Leu 740 745 750 Glu Thr Tyr Arg Thr His Arg Pro His Glu Gly Leu Tyr Gly Leu Tyr 755 760 765 Ser Glu Arg Ala Ser Pro Val Ala Leu Gly Leu Ile Leu Glu Ile Leu 770 775 780 Glu Pro Arg Gly Leu Asn Ile Leu Glu Gly Leu Ala Arg Gly Leu Glu 785 790 795 800 Gly Leu Asn Leu Glu Ala Arg Gly Gly Leu Leu Tyr Ser Ala Leu Ala 805 810 815 Leu Glu Gly Leu Tyr His Ile Ser Thr Tyr Arg Leu Tyr Ser Ala Ser 820 825 830 Pro Ile Leu Glu Ala Leu Ala Leu Tyr Ser Ala Arg Gly Leu Glu Ala 835 840 845 Ser Asn Ala Ser Asn Ile Leu Glu Ala Ser Asn Leu Tyr Ser Thr His 850 855 860 Arg Ile Leu Glu Pro Arg Ser Glu Arg Ser Glu Arg Thr Arg Pro Ser 865 870 875 880 Glu Arg Ser Glu Arg Ala Ser Asn Ile Leu Glu Ala Ser Pro Leu Tyr 885 890 895 Ser Thr Tyr Arg Leu Tyr Ser Leu Tyr Ser Ile Leu Glu Pro His Glu 900 905 910 Ser Glu Arg Gly Leu Leu Tyr Ser Thr Tyr Arg Ala Ser Asn Pro His 915 920 925 Glu Ala Ser Pro Leu Tyr Ser Ala Ser Pro Ala Ser Asn Thr His Arg 930 935 940 Gly Leu Tyr Ala Ser Asn Pro His Glu Val Ala Leu Val Ala Leu Ala 945 950 955 960 Ser Asn Ile Leu Glu Ala Ser Pro Leu Tyr Ser Pro His Glu Ala Ser 965 970 975 Asn Ser Glu Arg Leu Glu Thr Tyr Arg Ser Glu Arg Ala Ser Pro Leu 980 985 990 Glu Thr His Arg Ala Ser Asn Val Ala Leu Met Glu Thr Ser Glu Arg 995 1000 1005 Gly Leu Val Ala Leu Val Ala Leu Thr Tyr Arg Ser Glu Arg Ser Glu 1010 1015 1020 Arg Gly Leu Asn Thr Tyr Arg Ala Ser Asn Val Ala Leu Leu Tyr Ser 1025 1030 1035 1040 Ala Ser Asn Ala Arg Gly Thr His Arg His Ile Ser Thr Tyr Arg Pro 1045 1050 1055 His Glu Ser Glu Arg Leu Tyr Ser His Ile Ser Thr Tyr Arg Leu Glu 1060 1065 1070 Pro Arg Val Ala Leu Pro His Glu Ala Leu Ala Ala Ser Asn Ile Leu 1075 1080 1085 Glu Leu Glu Ala Ser Pro Ala Ser Pro Ala Ser Asn Ile Leu Glu Thr 1090 1095 1100 Tyr Arg Thr His Arg Ile Leu Glu Ile Leu Glu Ala Ser Asn Gly Leu 1105 1110 1115 1120 Tyr Pro His Glu Ala Ser Asn Leu Glu Thr His Arg Thr His Arg Leu 1125 1130 1135 Tyr Ser Gly Leu Tyr Pro His Glu Ala Ser Asn Ile Leu Glu Gly Leu 1140 1145 1150 Ala Ser Asn Ser Glu Arg Gly Leu Tyr Gly Leu Asn Ala Ser Asn Ile 1155 1160 1165 Leu Glu Gly Leu Ala Arg Gly Ala Ser Asn Pro Arg Ala Leu Ala Leu 1170 1175 1180 Glu Gly Leu Asn Leu Tyr Ser Leu Glu Ser Glu Arg Ser Glu Arg Gly 1185 1190 1195 1200 Leu Ser Glu Arg Val Ala Leu Val Ala Leu Ala Ser Pro Leu Glu Pro 1205 1210 1215 His Glu Thr His Arg Leu Tyr Ser Val Ala Leu Cys Tyr Ser Leu Glu 1220 1225 1230 Ala Arg Gly Leu Glu Thr His Arg Ala Arg Gly Ala Ser Asn Ser Glu 1235 1240 1245 Arg Ala Arg Gly Ala Ser Pro Ala Ser Pro Ser Glu Arg Thr His Arg 1250 1255 1260 Cys Tyr Ser Ile Leu Glu Gly Leu Asn Val Ala Leu Leu Tyr Ser Ala 1265 1270 1275 1280 Ser Asn Ala Ser Asn Thr His Arg Leu Glu Pro Arg Thr Tyr Arg Val 1285 1290 1295 Ala Leu Ala Leu Ala Ala Ser Pro Leu Tyr Ser Ala Ser Pro Ser Glu 1300 1305 1310 Arg Ile Leu Glu Ser Glu Arg Gly Leu Asn Gly Leu Ile Leu Glu Pro 1315 1320 1325 His Glu Gly Leu Ser Glu Arg Gly Leu Asn Ile Leu Glu Ile Leu Glu 1330 1335 1340 Thr His Arg Ala Ser Pro Gly Leu Thr His Arg Ala Ser Asn Val Ala 1345 1350 1355 1360 Leu Gly Leu Ala Ser Asn Thr Tyr Arg Ser Glu Arg Ala Ser Pro Ala 1365 1370 1375 Ser Asn Pro His Glu Ser Glu Arg Leu Glu Ala Ser Pro Gly Leu Ser 1380 1385 1390 Glu Arg Ile Leu Glu Leu Glu Ala Ser Pro Ala Leu Ala Leu Tyr Ser 1395 1400 1405 Val Ala Leu Pro Arg Thr His Arg Ala Ser Asn Pro Arg Gly Leu Ala 1410 1415 1420 Leu Ala Val Ala Leu Ala Ser Pro Pro Arg Leu Glu Leu Glu Pro Arg 1425 1430 1435 1440 Ala Ser Asn Val Ala Leu Ala Ser Asn Met Glu Thr Gly Leu Pro Arg 1445 1450 1455 Leu Glu Ala Ser Asn Val Ala Leu Pro Arg Gly Leu Tyr Gly Leu Gly 1460 1465 1470 Leu Gly Leu Val Ala Leu Pro His Glu Thr Tyr Arg Ala Ser Pro Ala 1475 1480 1485 Ser Pro Ile Leu Glu Thr His Arg Leu Tyr Ser Ala Ser Pro Val Ala 1490 1495 1500 Leu Ala Ser Pro Thr Tyr Arg Leu Glu Ala Ser Asn Ser Glu Arg Thr 1505 1510 1515 1520 Tyr Arg Thr Tyr Arg Thr Tyr Arg Leu Glu Gly Leu Ala Leu Ala Gly 1525 1530 1535 Leu Asn Leu Tyr Ser Leu Glu Ser Glu Arg Ala Ser Asn Ala Ser Asn 1540 1545 1550 Val Ala Leu Gly Leu Ala Ser Asn Ile Leu Glu Thr His Arg Leu Glu 1555 1560 1565 Thr His Arg Thr His Arg Ser Glu Arg Val Ala Leu Gly Leu Gly Leu 1570 1575 1580 Ala Leu Ala Leu Glu Gly Leu Tyr Thr Tyr Arg Ser Glu Arg Ala Ser 1585 1590 1595 1600 Asn Leu Tyr Ser Ile Leu Glu Thr Tyr Arg Thr His Arg Pro His Glu 1605 1610 1615 Leu Glu Pro Arg Ser Glu Arg Leu Glu Ala Leu Ala Gly Leu Leu Tyr 1620 1625 1630 Ser Val Ala Leu Ala Ser Asn Leu Tyr Ser Gly Leu Tyr Val Ala Leu 1635 1640 1645 Gly Leu Asn Ala Leu Ala Gly Leu Tyr Leu Glu Pro His Glu Leu Glu 1650 1655 1660 Ala Ser Asn Thr Arg Pro Ala Leu Ala Ala Ser Asn Gly Leu Val Ala 1665 1670 1675 1680 Leu Val Ala Leu Gly Leu Ala Ser Pro Pro His Glu Thr His Arg Thr 1685 1690 1695 His Arg Ala Ser Asn Ile Leu Glu Met Glu Thr Leu Tyr Ser Leu Tyr 1700 1705 1710 Ser Ala Ser Pro Thr His Arg Leu Glu Ala Ser Pro Leu Tyr Ser Ile 1715 1720 1725 Leu Glu Ser Glu Arg Ala Ser Pro Val Ala Leu Ser Glu Arg Ala Leu 1730 1735 1740 Ala Ile Leu Glu Ile Leu Glu Pro Arg Thr Tyr Arg Ile Leu Glu Gly 1745 1750 1755 1760 Leu Tyr Pro Arg Ala Leu Ala Leu Glu Ala Ser Asn Ile Leu Glu Gly 1765 1770 1775 Leu Tyr Ala Ser Asn Ser Glu Arg Ala Leu Ala Leu Glu Ala Arg Gly 1780 1785 1790 Gly Leu Tyr Ala Ser Asn Pro His Glu Leu Tyr Ser Gly Leu Asn Ala 1795 1800 1805 Leu Ala Pro His Glu Ala Leu Ala Thr His Arg Ala Leu Ala Gly Leu 1810 1815 1820 Tyr Val Ala Leu Ala Leu Ala Pro His Glu Leu Glu Leu Glu Gly Leu 1825 1830 1835 1840 Gly Leu Tyr Pro His Glu Pro Arg Gly Leu Pro His Glu Thr His Arg 1845 1850 1855 Ile Leu Glu Pro Arg Ala Leu Ala Leu Glu Gly Leu Tyr Val Ala Leu 1860 1865 1870 Pro His Glu Thr His Arg Pro His Glu Thr Tyr Arg Ser Glu Arg Ser 1875 1880 1885 Glu Arg Ile Leu Glu Gly Leu Asn Gly Leu Ala Arg Gly Gly Leu Leu 1890 1895 1900 Tyr Ser Ile Leu Glu Ile Leu Glu Leu Tyr Ser Thr His Arg Ile Leu 1905 1910 1915 1920 Glu Gly Leu Ala Ser Asn Cys Tyr Ser Leu Glu Gly Leu Gly Leu Asn 1925 1930 1935 Ala Arg Gly Val Ala Leu Leu Tyr Ser Ala Arg Gly Thr Arg Pro Leu 1940 1945 1950 Tyr Ser Ala Ser Pro Ser Glu Arg Thr Tyr Arg Gly Leu Asn Thr Arg 1955 1960 1965 Pro Met Glu Thr Val Ala Leu Ser Glu Arg Ala Ser Asn Thr Arg Pro 1970 1975 1980 Leu Glu Ser Glu Arg Ala Arg Gly Ile Leu Glu Thr His Arg Thr His 1985 1990 1995 2000 Arg Ala Arg Gly Pro His Glu Ala Ser Asn His Ile Ser Ile Leu Glu 2005 2010 2015 Ser Glu Arg Thr Tyr Arg Gly Leu Asn Met Glu Thr Thr Tyr Arg Ala 2020 2025 2030 Ser Pro Ser Glu Arg Leu Glu Ser Glu Arg Thr Tyr Arg Gly Leu Asn 2035 2040 2045 Ala Leu Ala Ala Ser Pro Ala Leu Ala Ile Leu Glu Leu Tyr Ser Ala 2050 2055 2060 Leu Ala Leu Tyr Ser Ile Leu Glu Ala Ser Pro Leu Glu Gly Leu Thr 2065 2070 2075 2080 Tyr Arg Leu Tyr Ser Leu Tyr Ser Thr Tyr Arg Ser Glu Arg Gly Leu 2085 2090 2095 Tyr Ser Glu Arg Ala Ser Pro Leu Tyr Ser Gly Leu Ala Ser Asn Ile 2100 2105 2110 Leu Glu Leu Tyr Ser Ser Glu Arg Gly Leu Asn Val Ala Leu Gly Leu 2115 2120 2125 Ala Ser Asn Leu Glu Leu Tyr Ser Ala Ser Asn Ser Glu Arg Leu Glu 2130 2135 2140 Ala Ser Pro Val Ala Leu Leu Tyr Ser Ile Leu Glu Ser Glu Arg Gly 2145 2150 2155 2160 Leu Ala Leu Ala Met Glu Thr Ala Ser Asn Ala Ser Asn Ile Leu Glu 2165 2170 2175 Ala Ser Asn Leu Tyr Ser Pro His Glu Ile Leu Glu Ala Arg Gly Gly 2180 2185 2190 Leu Cys Tyr Ser Ser Glu Arg Val Ala Leu Thr His Arg Thr Tyr Arg 2195 2200 2205 Leu Glu Pro His Glu Leu Tyr Ser Ala Ser Asn Met Glu Thr Leu Glu 2210 2215 2220 Pro Arg Leu Tyr Ser Val Ala Leu Ile Leu Glu Ala Ser Pro Gly Leu 2225 2230 2235 2240 Leu Glu Ala Ser Asn Leu Tyr Ser Pro His Glu Ala Ser Pro Leu Glu 2245 2250 2255 Leu Tyr Ser Thr His Arg Leu Tyr Ser Thr His Arg Gly Leu Leu Glu 2260 2265 2270 Ile Leu Glu Ala Ser Asn Leu Glu Ile Leu Glu Ala Ser Pro Ser Glu 2275 2280 2285 Arg His Ile Ser Ala Ser Asn Ile Leu Glu Ile Leu Glu Leu Glu Val 2290 2295 2300 Ala Leu Gly Leu Tyr Gly Leu Val Ala Leu Ala Ser Pro Ala Arg Gly 2305 2310 2315 2320 Leu Glu Leu Tyr Ser Ala Leu Ala Leu Tyr Ser Val Ala Leu Ala Ser 2325 2330 2335 Asn Gly Leu Ser Glu Arg Pro His Glu Gly Leu Ala Ser Asn Thr His 2340 2345 2350 Arg Ile Leu Glu Pro Arg Pro His Glu Ala Ser Asn Ile Leu Glu Pro 2355 2360 2365 His Glu Ser Glu Arg Thr Tyr Arg Thr His Arg Ala Ser Asn Ala Ser 2370 2375 2380 Asn Ser Glu Arg Leu Glu Leu Glu Leu Tyr Ser Ala Ser Pro Met Glu 2385 2390 2395 2400 Thr Ile Leu Glu Ala Ser Asn Gly Leu Thr Tyr Arg Pro His Glu Ala 2405 2410 2415 Ser Asn Ser Glu Arg Ile Leu Glu Ala Ser Asn Ala Ser Pro Ser Glu 2420 2425 2430 Arg Leu Tyr Ser Ile Leu Glu Leu Glu Ser Glu Arg Leu Glu Gly Leu 2435 2440 2445 Asn Ala Ser Asn Leu Tyr Ser Leu Tyr Ser Ala Ser Asn Thr His Arg 2450 2455 2460 Leu Glu Met Glu Thr Ala Ser Pro Thr His Arg Ser Glu Arg Gly Leu 2465 2470 2475 2480 Tyr Thr Tyr Arg Ala Ser Asn Ala Leu Ala Gly Leu Val Ala Leu Ala 2485 2490 2495 Arg Gly Val Ala Leu Gly Leu Gly Leu Tyr Ala Ser Asn Val Ala Leu 2500 2505 2510 Gly Leu Asn Leu Glu Ala Ser Asn Pro Arg Ile Leu Glu Pro His Glu 2515 2520 2525 Pro Arg Pro His Glu Ala Ser Pro Pro His Glu Leu Tyr Ser Leu Glu 2530 2535 2540 Gly Leu Tyr Ser Glu Arg Ser Glu Arg Gly Leu Tyr Ala Ser Pro Ala 2545 2550 2555 2560 Ser Pro Ala Arg Gly Gly Leu Tyr Leu Tyr Ser Val Ala Leu Ile Leu 2565 2570 2575 Glu Val Ala Leu Thr His Arg Gly Leu Asn Ala Ser Asn Gly Leu Ala 2580 2585 2590 Ser Asn Ile Leu Glu Val Ala Leu Thr Tyr Arg Ala Ser Asn Ala Leu 2595 2600 2605 Ala Met Glu Thr Thr Tyr Arg Gly Leu Ser Glu Arg Pro His Glu Ser 2610 2615 2620 Glu Arg Ile Leu Glu Ser Glu Arg Pro His Glu Thr Arg Pro Ile Leu 2625 2630 2635 2640 Glu Ala Arg Gly Ile Leu Glu Ala Ser Asn Leu Tyr Ser Thr Arg Pro 2645 2650 2655 Val Ala Leu Ser Glu Arg Ala Ser Asn Leu Glu Pro Arg Gly Leu Tyr 2660 2665 2670 Thr Tyr Arg Thr His Arg Ile Leu Glu Ile Leu Glu Ala Ser Pro Ser 2675 2680 2685 Glu Arg Val Ala Leu Leu Tyr Ser Ala Ser Asn Ala Ser Asn Ser Glu 2690 2695 2700 Arg Gly Leu Tyr Thr Arg Pro Ser Glu Arg Ile Leu Glu Gly Leu Tyr 2705 2710 2715 2720 Ile Leu Glu Ile Leu Glu Ser Glu Arg Ala Ser Asn Pro His Glu Leu 2725 2730 2735 Glu Val Ala Leu Pro His Glu Thr His Arg Leu Glu Leu Tyr Ser Gly 2740 2745 2750 Leu Asn Ala Ser Asn Gly Leu Ala Ser Asn Ser Glu Arg Gly Leu Gly 2755 2760 2765 Leu Asn Ala Ser Pro Ile Leu Glu Ala Ser Asn Pro His Glu Ser Glu 2770 2775 2780 Arg Thr Tyr Arg Ala Ser Pro Ile Leu Glu Ser Glu Arg Leu Tyr Ser 2785 2790 2795 2800 Ala Ser Asn Ala Leu Ala Ala Leu Ala Gly Leu Tyr Thr Tyr Arg Ala 2805 2810 2815 Ser Asn Leu Tyr Ser Thr Arg Pro Pro His Glu Pro His Glu Val Ala 2820 2825 2830 Leu Thr His Arg Ile Leu Glu Thr His Arg Thr His Arg Ala Ser Asn 2835 2840 2845 Met Glu Thr Met Glu Thr Gly Leu Tyr Ala Ser Asn Met Glu Thr Met 2850 2855 2860 Glu Thr Ile Leu Glu Thr Tyr Arg Ile Leu Glu Ala Ser Asn Gly Leu 2865 2870 2875 2880 Tyr Leu Tyr Ser Leu Glu Ile Leu Glu Ala Ser Pro Thr His Arg Ile 2885 2890 2895 Leu Glu Leu Tyr Ser Val Ala Leu Leu Tyr Ser Gly Leu Leu Glu Thr 2900 2905 2910 His Arg Gly Leu Tyr Ile Leu Glu Ala Ser Asn Pro His Glu Ser Glu 2915 2920 2925 Arg Leu Tyr Ser Thr His Arg Ile Leu Glu Thr His Arg Pro His Glu 2930 2935 2940 Gly Leu Asn Met Glu Thr Ala Ser Asn Leu Tyr Ser Ile Leu Glu Pro 2945 2950 2955 2960 Arg Ala Ser Asn Thr His Arg Gly Leu Tyr Leu Glu Ile Leu Glu Thr 2965 2970 2975 His Arg Ser Glu Arg Ala Ser Pro Ser Glu Arg Ala Ser Pro Ala Ser 2980 2985 2990 Asn Ile Leu Glu Ala Ser Asn Met Glu Thr Thr Arg Pro Ile Leu Glu 2995 3000 3005 Ala Arg Gly Ala Ser Pro Pro His Glu Thr Tyr Arg Ile Leu Glu Pro 3010 3015 3020 His Glu Ala Leu Ala Leu Tyr Ser Gly Leu Leu Glu Ala Ser Pro Ala 3025 3030 3035 3040 Ser Pro Leu Tyr Ser Ala Ser Pro Ile Leu Glu Ala Ser Asn Ile Leu 3045 3050 3055 Glu Leu Glu Pro His Glu Ala Ser Asn Ser Glu Arg Leu Glu Gly Leu 3060 3065 3070 Asn Thr Tyr Arg Thr His Arg Ala Ser Asn Val Ala Leu Val Ala Leu 3075 3080 3085 Leu Tyr Ser Ala Ser Pro Thr Tyr Arg Thr Arg Pro Gly Leu Tyr Ala 3090 3095 3100 Ser Asn Ala Ser Pro Leu Glu Ala Arg Gly Thr Tyr Arg Ala Ser Pro 3105 3110 3115 3120 Leu Tyr Ser Gly Leu Thr Tyr Arg Thr Tyr Arg Met Glu Thr Ile Leu 3125 3130 3135 Glu Ala Ser Asn Val Ala Leu Ala Ser Asn Thr Tyr Arg Met Glu Thr 3140 3145 3150 Ala Ser Asn Ala Arg Gly Thr Tyr Arg Met Glu Thr Ser Glu Arg Leu 3155 3160 3165 Tyr Ser Leu Tyr Ser Gly Leu Tyr Ala Ser Asn Gly Leu Tyr Ile Leu 3170 3175 3180 Glu Val Ala Leu Pro His Glu Ala Ser Asn Thr His Arg Ala Arg Gly 3185 3190 3195 3200 Leu Tyr Ser Ala Ser Asn Ala Ser Asn Ala Ser Asn Ala Ser Pro Pro 3205 3210 3215 His Glu Ala Ser Asn Gly Leu Gly Leu Tyr Thr Tyr Arg Leu Tyr Ser 3220 3225 3230 Ile Leu Glu Ile Leu Glu Ile Leu Glu Leu Tyr Ser Ala Arg Gly Ile 3235 3240 3245 Leu Glu Ala Arg Gly Gly Leu Tyr Ala Ser Asn Thr His Arg Ala Ser 3250 3255 3260 Asn Ala Ser Pro Thr His Arg Ala Arg Gly Val Ala Leu Ala Arg Gly 3265 3270 3275 3280 Gly Leu Tyr Gly Leu Ala Ser Asn Val Ala Leu Leu Glu Thr Tyr Arg 3285 3290 3295 Pro His Glu Ala Ser Asn Thr His Arg Thr His Arg Ile Leu Glu Ala 3300 3305 3310 Ser Pro Ala Ser Asn Leu Tyr Ser Gly Leu Asn Thr Tyr Arg Ser Glu 3315 3320 3325 Arg Leu Glu Gly Leu Tyr Met Glu Thr Thr Tyr Arg Leu Tyr Ser Pro 3330 3335 3340 Arg Ser Glu Arg Ala Arg Gly Ala Ser Asn Leu Glu Gly Leu Tyr Thr 3345 3350 3355 3360 His Arg Ala Ser Pro Leu Glu Val Ala Leu Pro Arg Leu Glu Gly Leu 3365 3370 3375 Tyr Ala Leu Ala Leu Glu Ala Ser Pro Gly Leu Asn Pro Arg Met Glu 3380 3385 3390 Thr Ala Ser Pro Gly Leu Ile Leu Glu Ala Arg Gly Leu Tyr Ser Thr 3395 3400 3405 Tyr Arg Gly Leu Tyr Ser Glu Arg Pro His Glu Ile Leu Glu Ile Leu 3410 3415 3420 Glu Gly Leu Asn Pro Arg Cys Tyr Ser Ala Ser Asn Thr His Arg Pro 3425 3430 3435 3440 His Glu Ala Ser Pro Thr Tyr Arg Thr Tyr Arg Ala Leu Ala Ser Glu 3445 3450 3455 Arg Gly Leu Asn Leu Glu Pro His Glu Leu Glu Ser Glu Arg Ser Glu 3460 3465 3470 Arg Ala Ser Asn Ala Leu Ala Thr His Arg Thr His Arg Ala Ser Asn 3475 3480 3485 Ala Arg Gly Leu Glu Gly Leu Tyr Ile Leu Glu Leu Glu Ser Glu Arg 3490 3495 3500 Ile Leu Glu Gly Leu Tyr Ser Glu Arg Thr Tyr Arg Ser Glu Arg Pro 3505 3510 3515 3520 His Glu Leu Tyr Ser Leu Glu Gly Leu Tyr Ala Ser Pro Ala Ser Pro 3525 3530 3535 Thr Tyr Arg Thr Arg Pro Pro His Glu Ala Ser Asn His Ile Ser Gly 3540 3545 3550 Leu Thr Tyr Arg Leu Glu Ile Leu Glu Pro Arg Val Ala Leu Ile Leu 3555 3560 3565 Glu Leu Tyr Ser Ile Leu Glu Gly Leu His Ile Ser Thr Tyr Arg Ala 3570 3575 3580 Leu Ala Ser Glu Arg Leu Glu Leu Glu Gly Leu Ser Glu Arg Thr His 3585 3590 3595 3600 Arg Ser Glu Arg Thr His Arg His Ile Ser Thr Arg Pro Val Ala Leu 3605 3610 3615 Pro His Glu Val Ala Leu Pro Arg Ala Leu Ala Ser Glu Arg Gly Leu 3620 3625 3630 <210> 9 <211> 3756 <212> DNA <213> Clostridium botulinum <400> 9 atgccaaaaa ttaatagttt taattataat gatcctgtta atgatagaac aattttatat 60 attaaaccag gcggttgtca agaattttat aaatcattta atattatgaa aaatatttgg 120 ataattccag agagaaatgt aattggtaca accccccaag attttcatcc gcctacttca 180 ttaaaaaatg gagatagtag ttattatgac cctaattatt tacaaagtga tgaagaaaag 240 gatagatttt taaaaatagt cacaaaaata tttaatagaa taaataataa tctttcagga 300 gggattttat tagaagaact gtcaaaagct aatccatatt tagggaatga taatactcca 360 gataatcaat tccatattgg tgatgcatca gcagttgaga ttaaattctc aaatggtagc 420 caagacatac tattacctaa tgttattata atgggagcag agcctgattt atttgaaact 480 aacagttcca atatttctct aagaaataat tatatgccaa gcaatcaccg ttttggatca 540 atagctatag taacattctc acctgaatat tcttttagat ttaatgataa ttgtatgaat 600 gaatttattc aagatcctgc tcttacatta atgcatgaat taatacattc attacatgga 660 ctatatgggg ctaaagggat tactacaaag tatactataa cacaaaaaca aaatccccta 720 ataacaaata taagaggtac aaatattgaa gaattcttaa cttttggagg tactgattta 780 aacattatta ctagtgctca gtccaatgat atctatacta atcttctagc tgattataaa 840 aaaatagcgt ctaaacttag caaagtacaa gtatctaatc cactacttaa tccttataaa 900 gatgtttttg aagcaaagta tggattagat aaagatgcta gcggaattta ttcggtaaat 960 ataaacaaat ttaatgatat ttttaaaaaa ttatacagct ttacggaatt tgatttacga 1020 actaaatttc aagttaaatg taggcaaact tatattggac agtataaata cttcaaactt 1080 tcaaacttgt taaatgattc tatttataat atatcagaag gctataatat aaataattta 1140 aaggtaaatt ttagaggaca gaatgcaaat ttaaatccta gaattattac accaattaca 1200 ggtagaggac tagtaaaaaa aatcattaga ttttgtaaaa atattgtttc tgtaaaaggc 1260 ataaggaaat caatatgtat cgaaataaat aatggtgagt tattttttgt ggcttccgag 1320 aatagttata atgatgataa tataaatact cctaaagaaa ttgacgatac agtaacttca 1380 aataataatt atgaaaatga tttagatcag gttattttaa attttaatag tgaatcagca 1440 cctggacttt cagatgaaaa attaaattta actatccaaa atgatgctta tataccaaaa 1500 tatgattcta atggaacaag tgatatagaa caacatgatg ttaatgaact taatgtattt 1560 ttctatttag atgcacagaa agtgcccgaa ggtgaaaata atgtcaatct cacctcttca 1620 attgatacag cattattaga acaacctaaa atatatacat ttttttcatc agaatttatt 1680 aataatgtca ataaacctgt gcaagcagca ttatttgtaa gctggataca acaagtgtta 1740 gtagatttta ctactgaagc taaccaaaaa agtactgttg ataaaattgc agatatttct 1800 atagttgttc catatatagg tcttgcttta aatataggaa atgaagcaca aaaaggaaat 1860 tttaaagatg cacttgaatt attaggagca ggtattttat tagaatttga acccgagctt 1920 ttaattccta caattttagt attcacgata aaatcttttt taggttcatc tgataataaa 1980 aataaagtta ttaaagcaat aaataatgca ttgaaagaaa gagatgaaaa atggaaagaa 2040 gtatatagtt ttatagtatc gaattggatg actaaaatta atacacaatt taataaaaga 2100 aaagaacaaa tgtatcaagc tttacaaaat caagtaaatg caattaaaac aataatagaa 2160 tctaagtata atagttatac tttagaggaa aaaaatgagc ttacaaataa atatgatatt 2220 aagcaaatag aaaatgaact taatcaaaag gtttctatag caatgaataa tatagacagg 2280 ttcttaactg aaagttctat atcctattta atgaaaataa taaatgaagt aaaaattaat 2340 aaattaagag aatatgatga gaatgtcaaa acgtatttat tgaattatat tatacaacat 2400 ggatcaatct tgggagagag tcagcaagaa ctaaattcta tggtaactga taccctaaat 2460 aatagtattc cttttaagct ttcttcttat acagatgata aaattttaat ttcatatttt 2520 aataaattct ttaagagaat taaaagtagt tcagttttaa atatgagata taaaaatgat 2580 aaatacgtag atacttcagg atatgattca aatataaata ttaatggaga tgtatataaa 2640 tatccaacta ataaaaatca atttggaata tataatgata aacttagtga agttaatata 2700 tctcaaaatg attacattat atatgataat aaatataaaa attttagtat tagtttttgg 2760 gtaagaattc ctaactatga taataagata gtaaatgtta ataatgaata cactataata 2820 aattgtatga gagataataa ttcaggatgg aaagtatctc ttaatcataa tgaaataatt 2880 tggacattcg aagataatcg aggaattaat caaaaattag catttaacta tggtaacgca 2940 aatggtattt ctgattatat aaataagtgg atttttgtaa ctataactaa tgatagatta 3000 ggagattcta aactttatat taatggaaat ttaatagatc aaaaatcaat tttaaattta 3060 ggtaatattc atgttagtga caatatatta tttaaaatag ttaattgtag ttatacaaga 3120 tatattggta ttagatattt taatattttt gataaagaat tagatgaaac agaaattcaa 3180 actttatata gcaatgaacc taatacaaat attttgaagg atttttgggg aaattatttg 3240 ctttatgaca aagaatacta tttattaaat gtgttaaaac caaataactt tattgatagg 3300 agaaaagatt ctactttaag cattaataat ataagaagca ctattctttt agctaataga 3360 ttatatagtg gaataaaagt taaaatacaa agagttaata atagtagtac taacgataat 3420 cttgttagaa agaatgatca ggtatatatt aattttgtag ccagcaaaac tcacttattt 3480 ccattatatg ctgatacagc taccacaaat aaagagaaaa caataaaaat atcatcatct 3540 ggcaatagat ttaatcaagt agtagttatg aattcagtag gaaattgtac aatgaatttt 3600 aaaaataata atggaaataa tattgggttg ttaggtttca aggcagatac tgtcgttgct 3660 agtacttggt attatacaca tatgagagat catacaaaca gcaatggatg tttttggaac 3720 tttatttctg aagaacatgg atggcaagaa aaataa 3756 <210> 10 <211> 3552 <212> PRT <213> Clostridium botulinum <400> 10 Met Glu Thr Pro Arg Leu Tyr Ser Ile Leu Glu Ala Ser Asn Ser Glu 1 5 10 15 Arg Pro His Glu Ala Ser Asn Thr Tyr Arg Ala Ser Asn Ala Ser Pro 20 25 30 Pro Arg Val Ala Leu Ala Ser Asn Ala Ser Pro Ala Arg Gly Thr His 35 40 45 Arg Ile Leu Glu Leu Glu Thr Tyr Arg Ile Leu Glu Leu Tyr Ser Pro 50 55 60 Arg Gly Leu Tyr Gly Leu Tyr Cys Tyr Ser Gly Leu Asn Gly Leu Pro 65 70 75 80 His Glu Thr Tyr Arg Leu Tyr Ser Ser Glu Arg Pro His Glu Ala Ser 85 90 95 Asn Ile Leu Glu Met Glu Thr Leu Tyr Ser Ala Ser Asn Ile Leu Glu 100 105 110 Thr Arg Pro Ile Leu Glu Ile Leu Glu Pro Arg Gly Leu Ala Arg Gly 115 120 125 Ala Ser Asn Val Ala Leu Ile Leu Glu Gly Leu Tyr Thr His Arg Thr 130 135 140 His Arg Pro Arg Gly Leu Asn Ala Ser Pro Pro His Glu His Ile Ser 145 150 155 160 Pro Arg Pro Arg Thr His Arg Ser Glu Arg Leu Glu Leu Tyr Ser Ala 165 170 175 Ser Asn Gly Leu Tyr Ala Ser Pro Ser Glu Arg Ser Glu Arg Thr Tyr 180 185 190 Arg Thr Tyr Arg Ala Ser Pro Pro Arg Ala Ser Asn Thr Tyr Arg Leu 195 200 205 Glu Gly Leu Asn Ser Glu Arg Ala Ser Pro Gly Leu Gly Leu Leu Tyr 210 215 220 Ser Ala Ser Pro Ala Arg Gly Pro His Glu Leu Glu Leu Tyr Ser Ile 225 230 235 240 Leu Glu Val Ala Leu Thr His Arg Leu Tyr Ser Ile Leu Glu Pro His 245 250 255 Glu Ala Ser Asn Ala Arg Gly Ile Leu Glu Ala Ser Asn Ala Ser Asn 260 265 270 Ala Ser Asn Leu Glu Ser Glu Arg Gly Leu Tyr Gly Leu Tyr Ile Leu 275 280 285 Glu Leu Glu Leu Glu Gly Leu Gly Leu Leu Glu Ser Glu Arg Leu Tyr 290 295 300 Ser Ala Leu Ala Ala Ser Asn Pro Arg Thr Tyr Arg Leu Glu Gly Leu 305 310 315 320 Tyr Ala Ser Asn Ala Ser Pro Ala Ser Asn Thr His Arg Pro Arg Ala 325 330 335 Ser Pro Ala Ser Asn Gly Leu Asn Pro His Glu His Ile Ser Ile Leu 340 345 350 Glu Gly Leu Tyr Ala Ser Pro Ala Leu Ala Ser Glu Arg Ala Leu Ala 355 360 365 Val Ala Leu Gly Leu Ile Leu Glu Leu Tyr Ser Pro His Glu Ser Glu 370 375 380 Arg Ala Ser Asn Gly Leu Tyr Ser Glu Arg Gly Leu Asn Ala Ser Pro 385 390 395 400 Ile Leu Glu Leu Glu Leu Glu Pro Arg Ala Ser Asn Val Ala Leu Ile 405 410 415 Leu Glu Ile Leu Glu Met Glu Thr Gly Leu Tyr Ala Leu Ala Gly Leu 420 425 430 Pro Arg Ala Ser Pro Leu Glu Pro His Glu Gly Leu Thr His Arg Ala 435 440 445 Ser Asn Ser Glu Arg Ser Glu Arg Ala Ser Asn Ile Leu Glu Ser Glu 450 455 460 Arg Leu Glu Ala Arg Gly Ala Ser Asn Ala Ser Asn Thr Tyr Arg Met 465 470 475 480 Glu Thr Pro Arg Ser Glu Arg Ala Ser Asn His Ile Ser Ala Arg Gly 485 490 495 Pro His Glu Gly Leu Tyr Ser Glu Arg Ile Leu Glu Ala Leu Ala Ile 500 505 510 Leu Glu Val Ala Leu Thr His Arg Pro His Glu Ser Glu Arg Pro Arg 515 520 525 Gly Leu Thr Tyr Arg Ser Glu Arg Pro His Glu Ala Arg Gly Pro His 530 535 540 Glu Ala Ser Asn Ala Ser Pro Ala Ser Asn Cys Tyr Ser Met Glu Thr 545 550 555 560 Ala Ser Asn Gly Leu Pro His Glu Ile Leu Glu Gly Leu Asn Ala Ser 565 570 575 Pro Pro Arg Ala Leu Ala Leu Glu Thr His Arg Leu Glu Met Glu Thr 580 585 590 His Ile Ser Gly Leu Leu Glu Ile Leu Glu His Ile Ser Ser Glu Arg 595 600 605 Leu Glu His Ile Ser Gly Leu Tyr Leu Glu Thr Tyr Arg Gly Leu Tyr 610 615 620 Ala Leu Ala Leu Tyr Ser Gly Leu Tyr Ile Leu Glu Thr His Arg Thr 625 630 635 640 His Arg Leu Tyr Ser Thr Tyr Arg Thr His Arg Ile Leu Glu Thr His 645 650 655 Arg Gly Leu Asn Leu Tyr Ser Gly Leu Asn Ala Ser Asn Pro Arg Leu 660 665 670 Glu Ile Leu Glu Thr His Arg Ala Ser Asn Ile Leu Glu Ala Arg Gly 675 680 685 Gly Leu Tyr Thr His Arg Ala Ser Asn Ile Leu Glu Gly Leu Gly Leu 690 695 700 Pro His Glu Leu Glu Thr His Arg Pro His Glu Gly Leu Tyr Gly Leu 705 710 715 720 Tyr Thr His Arg Ala Ser Pro Leu Glu Ala Ser Asn Ile Leu Glu Ile 725 730 735 Leu Glu Thr His Arg Ser Glu Arg Ala Leu Ala Gly Leu Asn Ser Glu 740 745 750 Arg Ala Ser Asn Ala Ser Pro Ile Leu Glu Thr Tyr Arg Thr His Arg 755 760 765 Ala Ser Asn Leu Glu Leu Glu Ala Leu Ala Ala Ser Pro Thr Tyr Arg 770 775 780 Leu Tyr Ser Leu Tyr Ser Ile Leu Glu Ala Leu Ala Ser Glu Arg Leu 785 790 795 800 Tyr Ser Leu Glu Ser Glu Arg Leu Tyr Ser Val Ala Leu Gly Leu Asn 805 810 815 Val Ala Leu Ser Glu Arg Ala Ser Asn Pro Arg Leu Glu Leu Glu Ala 820 825 830 Ser Asn Pro Arg Thr Tyr Arg Leu Tyr Ser Ala Ser Pro Val Ala Leu 835 840 845 Pro His Glu Gly Leu Ala Leu Ala Leu Tyr Ser Thr Tyr Arg Gly Leu 850 855 860 Tyr Leu Glu Ala Ser Pro Leu Tyr Ser Ala Ser Pro Ala Leu Ala Ser 865 870 875 880 Glu Arg Gly Leu Tyr Ile Leu Glu Thr Tyr Arg Ser Glu Arg Val Ala 885 890 895 Leu Ala Ser Asn Ile Leu Glu Ala Ser Asn Leu Tyr Ser Pro His Glu 900 905 910 Ala Ser Asn Ala Ser Pro Ile Leu Glu Pro His Glu Leu Tyr Ser Leu 915 920 925 Tyr Ser Leu Glu Thr Tyr Arg Ser Glu Arg Pro His Glu Thr His Arg 930 935 940 Gly Leu Pro His Glu Ala Ser Pro Leu Glu Ala Arg Gly Thr His Arg 945 950 955 960 Leu Tyr Ser Pro His Glu Gly Leu Asn Val Ala Leu Leu Tyr Ser Cys 965 970 975 Tyr Ser Ala Arg Gly Gly Leu Asn Thr His Arg Thr Tyr Arg Ile Leu 980 985 990 Glu Gly Leu Tyr Gly Leu Asn Thr Tyr Arg Leu Tyr Ser Thr Tyr Arg 995 1000 1005 Pro His Glu Leu Tyr Ser Leu Glu Ser Glu Arg Ala Ser Asn Leu Glu 1010 1015 1020 Leu Glu Ala Ser Asn Ala Ser Pro Ser Glu Arg Ile Leu Glu Thr Tyr 1025 1030 1035 1040 Arg Ala Ser Asn Ile Leu Glu Ser Glu Arg Gly Leu Gly Leu Tyr Thr 1045 1050 1055 Tyr Arg Ala Ser Asn Ile Leu Glu Ala Ser Asn Ala Ser Asn Leu Glu 1060 1065 1070 Leu Tyr Ser Val Ala Leu Ala Ser Asn Pro His Glu Ala Arg Gly Gly 1075 1080 1085 Leu Tyr Gly Leu Asn Ala Ser Asn Ala Leu Ala Ala Ser Asn Leu Glu 1090 1095 1100 Ala Ser Asn Pro Arg Ala Arg Gly Ile Leu Glu Ile Leu Glu Thr His 1105 1110 1115 1120 Arg Pro Arg Ile Leu Glu Thr His Arg Gly Leu Tyr Ala Arg Gly Gly 1125 1130 1135 Leu Tyr Leu Glu Val Ala Leu Leu Tyr Ser Leu Tyr Ser Ile Leu Glu 1140 1145 1150 Ile Leu Glu Ala Arg Gly Pro His Glu Cys Tyr Ser Leu Tyr Ser Ala 1155 1160 1165 Ser Asn Ile Leu Glu Val Ala Leu Ser Glu Arg Val Ala Leu Leu Tyr 1170 1175 1180 Ser Gly Leu Tyr Ile Leu Glu Ala Arg Gly Leu Tyr Ser Ser Glu Arg 1185 1190 1195 1200 Ile Leu Glu Cys Tyr Ser Ile Leu Glu Gly Leu Ile Leu Glu Ala Ser 1205 1210 1215 Asn Ala Ser Asn Gly Leu Tyr Gly Leu Leu Glu Pro His Glu Pro His 1220 1225 1230 Glu Val Ala Leu Ala Leu Ala Ser Glu Arg Gly Leu Ala Ser Asn Ser 1235 1240 1245 Glu Arg Thr Tyr Arg Ala Ser Asn Ala Ser Pro Ala Ser Pro Ala Ser 1250 1255 1260 Asn Ile Leu Glu Ala Ser Asn Thr His Arg Pro Arg Leu Tyr Ser Gly 1265 1270 1275 1280 Leu Ile Leu Glu Ala Ser Pro Ala Ser Pro Thr His Arg Val Ala Leu 1285 1290 1295 Thr His Arg Ser Glu Arg Ala Ser Asn Ala Ser Asn Ala Ser Asn Thr 1300 1305 1310 Tyr Arg Gly Leu Ala Ser Asn Ala Ser Pro Leu Glu Ala Ser Pro Gly 1315 1320 1325 Leu Asn Val Ala Leu Ile Leu Glu Leu Glu Ala Ser Asn Pro His Glu 1330 1335 1340 Ala Ser Asn Ser Glu Arg Gly Leu Ser Glu Arg Ala Leu Ala Pro Arg 1345 1350 1355 1360 Gly Leu Tyr Leu Glu Ser Glu Arg Ala Ser Pro Gly Leu Leu Tyr Ser 1365 1370 1375 Leu Glu Ala Ser Asn Leu Glu Thr His Arg Ile Leu Glu Gly Leu Asn 1380 1385 1390 Ala Ser Asn Ala Ser Pro Ala Leu Ala Thr Tyr Arg Ile Leu Glu Pro 1395 1400 1405 Arg Leu Tyr Ser Thr Tyr Arg Ala Ser Pro Ser Glu Arg Ala Ser Asn 1410 1415 1420 Gly Leu Tyr Thr His Arg Ser Glu Arg Ala Ser Pro Ile Leu Glu Gly 1425 1430 1435 1440 Leu Gly Leu Asn His Ile Ser Ala Ser Pro Val Ala Leu Ala Ser Asn 1445 1450 1455 Gly Leu Leu Glu Ala Ser Asn Val Ala Leu Pro His Glu Pro His Glu 1460 1465 1470 Thr Tyr Arg Leu Glu Ala Ser Pro Ala Leu Ala Gly Leu Asn Leu Tyr 1475 1480 1485 Ser Val Ala Leu Pro Arg Gly Leu Gly Leu Tyr Gly Leu Ala Ser Asn 1490 1495 1500 Ala Ser Asn Val Ala Leu Ala Ser Asn Leu Glu Thr His Arg Ser Glu 1505 1510 1515 1520 Arg Ser Glu Arg Ile Leu Glu Ala Ser Pro Thr His Arg Ala Leu Ala 1525 1530 1535 Leu Glu Leu Glu Gly Leu Gly Leu Asn Pro Arg Leu Tyr Ser Ile Leu 1540 1545 1550 Glu Thr Tyr Arg Thr His Arg Pro His Glu Pro His Glu Ser Glu Arg 1555 1560 1565 Ser Glu Arg Gly Leu Pro His Glu Ile Leu Glu Ala Ser Asn Ala Ser 1570 1575 1580 Asn Val Ala Leu Ala Ser Asn Leu Tyr Ser Pro Arg Val Ala Leu Gly 1585 1590 1595 1600 Leu Asn Ala Leu Ala Ala Leu Ala Leu Glu Pro His Glu Val Ala Leu 1605 1610 1615 Ser Glu Arg Thr Arg Pro Ile Leu Glu Gly Leu Asn Gly Leu Asn Val 1620 1625 1630 Ala Leu Leu Glu Val Ala Leu Ala Ser Pro Pro His Glu Thr His Arg 1635 1640 1645 Thr His Arg Gly Leu Ala Leu Ala Ala Ser Asn Gly Leu Asn Leu Tyr 1650 1655 1660 Ser Ser Glu Arg Thr His Arg Val Ala Leu Ala Ser Pro Leu Tyr Ser 1665 1670 1675 1680 Ile Leu Glu Ala Leu Ala Ala Ser Pro Ile Leu Glu Ser Glu Arg Ile 1685 1690 1695 Leu Glu Val Ala Leu Val Ala Leu Pro Arg Thr Tyr Arg Ile Leu Glu 1700 1705 1710 Gly Leu Tyr Leu Glu Ala Leu Ala Leu Glu Ala Ser Asn Ile Leu Glu 1715 1720 1725 Gly Leu Tyr Ala Ser Asn Gly Leu Ala Leu Ala Gly Leu Asn Leu Tyr 1730 1735 1740 Ser Gly Leu Tyr Ala Ser Asn Pro His Glu Leu Tyr Ser Ala Ser Pro 1745 1750 1755 1760 Ala Leu Ala Leu Glu Gly Leu Leu Glu Leu Glu Gly Leu Tyr Ala Leu 1765 1770 1775 Ala Gly Leu Tyr Ile Leu Glu Leu Glu Leu Glu Gly Leu Pro His Glu 1780 1785 1790 Gly Leu Pro Arg Gly Leu Leu Glu Leu Glu Ile Leu Glu Pro Arg Thr 1795 1800 1805 His Arg Ile Leu Glu Leu Glu Val Ala Leu Pro His Glu Thr His Arg 1810 1815 1820 Ile Leu Glu Leu Tyr Ser Ser Glu Arg Pro His Glu Leu Glu Gly Leu 1825 1830 1835 1840 Tyr Ser Glu Arg Ser Glu Arg Ala Ser Pro Ala Ser Asn Leu Tyr Ser 1845 1850 1855 Ala Ser Asn Leu Tyr Ser Val Ala Leu Ile Leu Glu Leu Tyr Ser Ala 1860 1865 1870 Leu Ala Ile Leu Glu Ala Ser Asn Ala Ser Asn Ala Leu Ala Leu Glu 1875 1880 1885 Leu Tyr Ser Gly Leu Ala Arg Gly Ala Ser Pro Gly Leu Leu Tyr Ser 1890 1895 1900 Thr Arg Pro Leu Tyr Ser Gly Leu Val Ala Leu Thr Tyr Arg Ser Glu 1905 1910 1915 1920 Arg Pro His Glu Ile Leu Glu Val Ala Leu Ser Glu Arg Ala Ser Asn 1925 1930 1935 Thr Arg Pro Met Glu Thr Thr His Arg Leu Tyr Ser Ile Leu Glu Ala 1940 1945 1950 Ser Asn Thr His Arg Gly Leu Asn Pro His Glu Ala Ser Asn Leu Tyr 1955 1960 1965 Ser Ala Arg Gly Leu Tyr Ser Gly Leu Gly Leu Asn Met Glu Thr Thr 1970 1975 1980 Tyr Arg Gly Leu Asn Ala Leu Ala Leu Glu Gly Leu Asn Ala Ser Asn 1985 1990 1995 2000 Gly Leu Asn Val Ala Leu Ala Ser Asn Ala Leu Ala Ile Leu Glu Leu 2005 2010 2015 Tyr Ser Thr His Arg Ile Leu Glu Ile Leu Glu Gly Leu Ser Glu Arg 2020 2025 2030 Leu Tyr Ser Thr Tyr Arg Ala Ser Asn Ser Glu Arg Thr Tyr Arg Thr 2035 2040 2045 His Arg Leu Glu Gly Leu Gly Leu Leu Tyr Ser Ala Ser Asn Gly Leu 2050 2055 2060 Leu Glu Thr His Arg Ala Ser Asn Leu Tyr Ser Thr Tyr Arg Ala Ser 2065 2070 2075 2080 Pro Ile Leu Glu Leu Tyr Ser Gly Leu Asn Ile Leu Glu Gly Leu Ala 2085 2090 2095 Ser Asn Gly Leu Leu Glu Ala Ser Asn Gly Leu Asn Leu Tyr Ser Val 2100 2105 2110 Ala Leu Ser Glu Arg Ile Leu Glu Ala Leu Ala Met Glu Thr Ala Ser 2115 2120 2125 Asn Ala Ser Asn Ile Leu Glu Ala Ser Pro Ala Arg Gly Pro His Glu 2130 2135 2140 Leu Glu Thr His Arg Gly Leu Ser Glu Arg Ser Glu Arg Ile Leu Glu 2145 2150 2155 2160 Ser Glu Arg Thr Tyr Arg Leu Glu Met Glu Thr Leu Tyr Ser Ile Leu 2165 2170 2175 Glu Ile Leu Glu Ala Ser Asn Gly Leu Val Ala Leu Leu Tyr Ser Ile 2180 2185 2190 Leu Glu Ala Ser Asn Leu Tyr Ser Leu Glu Ala Arg Gly Gly Leu Thr 2195 2200 2205 Tyr Arg Ala Ser Pro Gly Leu Ala Ser Asn Val Ala Leu Leu Tyr Ser 2210 2215 2220 Thr His Arg Thr Tyr Arg Leu Glu Leu Glu Ala Ser Asn Thr Tyr Arg 2225 2230 2235 2240 Ile Leu Glu Ile Leu Glu Gly Leu Asn His Ile Ser Gly Leu Tyr Ser 2245 2250 2255 Glu Arg Ile Leu Glu Leu Glu Gly Leu Tyr Gly Leu Ser Glu Arg Gly 2260 2265 2270 Leu Asn Gly Leu Asn Gly Leu Leu Glu Ala Ser Asn Ser Glu Arg Met 2275 2280 2285 Glu Thr Val Ala Leu Thr His Arg Ala Ser Pro Thr His Arg Leu Glu 2290 2295 2300 Ala Ser Asn Ala Ser Asn Ser Glu Arg Ile Leu Glu Pro Arg Pro His 2305 2310 2315 2320 Glu Leu Tyr Ser Leu Glu Ser Glu Arg Ser Glu Arg Thr Tyr Arg Thr 2325 2330 2335 His Arg Ala Ser Pro Ala Ser Pro Leu Tyr Ser Ile Leu Glu Leu Glu 2340 2345 2350 Ile Leu Glu Ser Glu Arg Thr Tyr Arg Pro His Glu Ala Ser Asn Leu 2355 2360 2365 Tyr Ser Pro His Glu Pro His Glu Leu Tyr Ser Ala Arg Gly Ile Leu 2370 2375 2380 Glu Leu Tyr Ser Ser Glu Arg Ser Glu Arg Ser Glu Arg Val Ala Leu 2385 2390 2395 2400 Leu Glu Ala Ser Asn Met Glu Thr Ala Arg Gly Thr Tyr Arg Leu Tyr 2405 2410 2415 Ser Ala Ser Asn Ala Ser Pro Leu Tyr Ser Thr Tyr Arg Val Ala Leu 2420 2425 2430 Ala Ser Pro Thr His Arg Ser Glu Arg Gly Leu Tyr Thr Tyr Arg Ala 2435 2440 2445 Ser Pro Ser Glu Arg Ala Ser Asn Ile Leu Glu Ala Ser Asn Ile Leu 2450 2455 2460 Glu Ala Ser Asn Gly Leu Tyr Ala Ser Pro Val Ala Leu Thr Tyr Arg 2465 2470 2475 2480 Leu Tyr Ser Thr Tyr Arg Pro Arg Thr His Arg Ala Ser Asn Leu Tyr 2485 2490 2495 Ser Ala Ser Asn Gly Leu Asn Pro His Glu Gly Leu Tyr Ile Leu Glu 2500 2505 2510 Thr Tyr Arg Ala Ser Asn Ala Ser Pro Leu Tyr Ser Leu Glu Ser Glu 2515 2520 2525 Arg Gly Leu Val Ala Leu Ala Ser Asn Ile Leu Glu Ser Glu Arg Gly 2530 2535 2540 Leu Asn Ala Ser Asn Ala Ser Pro Thr Tyr Arg Ile Leu Glu Ile Leu 2545 2550 2555 2560 Glu Thr Tyr Arg Ala Ser Pro Ala Ser Asn Leu Tyr Ser Thr Tyr Arg 2565 2570 2575 Leu Tyr Ser Ala Ser Asn Pro His Glu Ser Glu Arg Ile Leu Glu Ser 2580 2585 2590 Glu Arg Pro His Glu Thr Arg Pro Val Ala Leu Ala Arg Gly Ile Leu 2595 2600 2605 Glu Pro Arg Ala Ser Asn Thr Tyr Arg Ala Ser Pro Ala Ser Asn Leu 2610 2615 2620 Tyr Ser Ile Leu Glu Val Ala Leu Ala Ser Asn Val Ala Leu Ala Ser 2625 2630 2635 2640 Asn Ala Ser Asn Gly Leu Thr Tyr Arg Thr His Arg Ile Leu Glu Ile 2645 2650 2655 Leu Glu Ala Ser Asn Cys Tyr Ser Met Glu Thr Ala Arg Gly Ala Ser 2660 2665 2670 Pro Ala Ser Asn Ala Ser Asn Ser Glu Arg Gly Leu Tyr Thr Arg Pro 2675 2680 2685 Leu Tyr Ser Val Ala Leu Ser Glu Arg Leu Glu Ala Ser Asn His Ile 2690 2695 2700 Ser Ala Ser Asn Gly Leu Ile Leu Glu Ile Leu Glu Thr Arg Pro Thr 2705 2710 2715 2720 His Arg Pro His Glu Gly Leu Ala Ser Pro Ala Ser Asn Ala Arg Gly 2725 2730 2735 Gly Leu Tyr Ile Leu Glu Ala Ser Asn Gly Leu Asn Leu Tyr Ser Leu 2740 2745 2750 Glu Ala Leu Ala Pro His Glu Ala Ser Asn Thr Tyr Arg Gly Leu Tyr 2755 2760 2765 Ala Ser Asn Ala Leu Ala Ala Ser Asn Gly Leu Tyr Ile Leu Glu Ser 2770 2775 2780 Glu Arg Ala Ser Pro Thr Tyr Arg Ile Leu Glu Ala Ser Asn Leu Tyr 2785 2790 2795 2800 Ser Thr Arg Pro Ile Leu Glu Pro His Glu Val Ala Leu Thr His Arg 2805 2810 2815 Ile Leu Glu Thr His Arg Ala Ser Asn Ala Ser Pro Ala Arg Gly Leu 2820 2825 2830 Glu Gly Leu Tyr Ala Ser Pro Ser Glu Arg Leu Tyr Ser Leu Glu Thr 2835 2840 2845 Tyr Arg Ile Leu Glu Ala Ser Asn Gly Leu Tyr Ala Ser Asn Leu Glu 2850 2855 2860 Ile Leu Glu Ala Ser Pro Gly Leu Asn Leu Tyr Ser Ser Glu Arg Ile 2865 2870 2875 2880 Leu Glu Leu Glu Ala Ser Asn Leu Glu Gly Leu Tyr Ala Ser Asn Ile 2885 2890 2895 Leu Glu His Ile Ser Val Ala Leu Ser Glu Arg Ala Ser Pro Ala Ser 2900 2905 2910 Asn Ile Leu Glu Leu Glu Pro His Glu Leu Tyr Ser Ile Leu Glu Val 2915 2920 2925 Ala Leu Ala Ser Asn Cys Tyr Ser Ser Glu Arg Thr Tyr Arg Thr His 2930 2935 2940 Arg Ala Arg Gly Thr Tyr Arg Ile Leu Glu Gly Leu Tyr Ile Leu Glu 2945 2950 2955 2960 Ala Arg Gly Thr Tyr Arg Pro His Glu Ala Ser Asn Ile Leu Glu Pro 2965 2970 2975 His Glu Ala Ser Pro Leu Tyr Ser Gly Leu Leu Glu Ala Ser Pro Gly 2980 2985 2990 Leu Thr His Arg Gly Leu Ile Leu Glu Gly Leu Asn Thr His Arg Leu 2995 3000 3005 Glu Thr Tyr Arg Ser Glu Arg Ala Ser Asn Gly Leu Pro Arg Ala Ser 3010 3015 3020 Asn Thr His Arg Ala Ser Asn Ile Leu Glu Leu Glu Leu Tyr Ser Ala 3025 3030 3035 3040 Ser Pro Pro His Glu Thr Arg Pro Gly Leu Tyr Ala Ser Asn Thr Tyr 3045 3050 3055 Arg Leu Glu Leu Glu Thr Tyr Arg Ala Ser Pro Leu Tyr Ser Gly Leu 3060 3065 3070 Thr Tyr Arg Thr Tyr Arg Leu Glu Leu Glu Ala Ser Asn Val Ala Leu 3075 3080 3085 Leu Glu Leu Tyr Ser Pro Arg Ala Ser Asn Ala Ser Asn Pro His Glu 3090 3095 3100 Ile Leu Glu Ala Ser Pro Ala Arg Gly Ala Arg Gly Leu Tyr Ser Ala 3105 3110 3115 3120 Ser Pro Ser Glu Arg Thr His Arg Leu Glu Ser Glu Arg Ile Leu Glu 3125 3130 3135 Ala Ser Asn Ala Ser Asn Ile Leu Glu Ala Arg Gly Ser Glu Arg Thr 3140 3145 3150 His Arg Ile Leu Glu Leu Glu Leu Glu Ala Leu Ala Ala Ser Asn Ala 3155 3160 3165 Arg Gly Leu Glu Thr Tyr Arg Ser Glu Arg Gly Leu Tyr Ile Leu Glu 3170 3175 3180 Leu Tyr Ser Val Ala Leu Leu Tyr Ser Ile Leu Glu Gly Leu Asn Ala 3185 3190 3195 3200 Arg Gly Val Ala Leu Ala Ser Asn Ala Ser Asn Ser Glu Arg Ser Glu 3205 3210 3215 Arg Thr His Arg Ala Ser Asn Ala Ser Pro Ala Ser Asn Leu Glu Val 3220 3225 3230 Ala Leu Ala Arg Gly Leu Tyr Ser Ala Ser Asn Ala Ser Pro Gly Leu 3235 3240 3245 Asn Val Ala Leu Thr Tyr Arg Ile Leu Glu Ala Ser Asn Pro His Glu 3250 3255 3260 Val Ala Leu Ala Leu Ala Ser Glu Arg Leu Tyr Ser Thr His Arg His 3265 3270 3275 3280 Ile Ser Leu Glu Pro His Glu Pro Arg Leu Glu Thr Tyr Arg Ala Leu 3285 3290 3295 Ala Ala Ser Pro Thr His Arg Ala Leu Ala Thr His Arg Thr His Arg 3300 3305 3310 Ala Ser Asn Leu Tyr Ser Gly Leu Leu Tyr Ser Thr His Arg Ile Leu 3315 3320 3325 Glu Leu Tyr Ser Ile Leu Glu Ser Glu Arg Ser Glu Arg Ser Glu Arg 3330 3335 3340 Gly Leu Tyr Ala Ser Asn Ala Arg Gly Pro His Glu Ala Ser Asn Gly 3345 3350 3355 3360 Leu Asn Val Ala Leu Val Ala Leu Val Ala Leu Met Glu Thr Ala Ser 3365 3370 3375 Asn Ser Glu Arg Val Ala Leu Gly Leu Tyr Ala Ser Asn Cys Tyr Ser 3380 3385 3390 Thr His Arg Met Glu Thr Ala Ser Asn Pro His Glu Leu Tyr Ser Ala 3395 3400 3405 Ser Asn Ala Ser Asn Ala Ser Asn Gly Leu Tyr Ala Ser Asn Ala Ser 3410 3415 3420 Asn Ile Leu Glu Gly Leu Tyr Leu Glu Leu Glu Gly Leu Tyr Pro His 3425 3430 3435 3440 Glu Leu Tyr Ser Ala Leu Ala Ala Ser Pro Thr His Arg Val Ala Leu 3445 3450 3455 Val Ala Leu Ala Leu Ala Ser Glu Arg Thr His Arg Thr Arg Pro Thr 3460 3465 3470 Tyr Arg Thr Tyr Arg Thr His Arg His Ile Ser Met Glu Thr Ala Arg 3475 3480 3485 Gly Ala Ser Pro His Ile Ser Thr His Arg Ala Ser Asn Ser Glu Arg 3490 3495 3500 Ala Ser Asn Gly Leu Tyr Cys Tyr Ser Pro His Glu Thr Arg Pro Ala 3505 3510 3515 3520 Ser Asn Pro His Glu Ile Leu Glu Ser Glu Arg Gly Leu Gly Leu His 3525 3530 3535 Ile Ser Gly Leu Tyr Thr Arg Pro Gly Leu Asn Gly Leu Leu Tyr Ser 3540 3545 3550 <210> 11 <211> 3843 <212> DNA <213> Clostridium botulinum <400> 11 atgccagttg taataaatag ttttaattat aatgaccctg ttaatgatga gacaatttta 60 tacatgcaga aaccatatga agaaagaagt agaaaatatt ataaagcttt tgagattatg 120 cctaatgttt ggataatgcc tgagagagat acaataggaa ctaagcctga tgagtttcag 180 gtgccggatt cattaaagaa cggaagtagt gcttattatg atcctaatta tttaaccact 240 gatgctgaaa aagatagata tttaaaaaca atgataaaat tatttaatag aattaatagt 300 aatcctacag ggaaagtttt gttagaagaa gtatcaaatg ctagaccata tttaggagat 360 gatgacacgc taattaatga attccttcca gttaatgtaa ctacaagtgt taatataaaa 420 ttttcaactg atgttgaaag ttcaataata tcgaatcttc ttgtattggg agcaggacct 480 gatatattta aagcttactg tacccccctt gtaaggttta ataagtcaga taaattaatt 540 gaaccaagta atcatggttt tggatcaatt aatatcttga cattttcacc tgagtatgaa 600 catattttta atgatattag tggagggaat cataatagta cagaatcatt tattgcagat 660 cctgcaattt cactagctca tgaattgata catgcactac atggattata cggggctaag 720 gcagttactc ataaagagtc tctagtagca gagcgaggac ctcttatgat agccgaaaag 780 cccataaggc tagaagaatt tttaactttt ggaggtgagg atttaaatat cattcctagt 840 gctatgaagg aaaaaatata taacgatctt ttagctaact atgaaaaaat agctactaga 900 cttagagaag ttaatacggc tcctcctgga tatgatatta atgaatataa agattatttt 960 caatggaagt atggactaga tagaaatgca gatggaagtt atactgtgaa tagaaataaa 1020 tttaatgaaa tttataaaaa attatatagc tttacagaga ttgacttagc aaataaattt 1080 aaagtaaaat gtagaaatac ttattttatt aaatatggat ttgtaaaagt tccaaatttg 1140 ttagatgatg atatttatac tgtatcagag gggtttaata taggtaattt agcagtaaac 1200 aatcgcggac aaaatataaa tttaaatcct aaaattattg attccattcc agataaaggt 1260 ttagtggaaa agattattaa attttgtaag agcattattc ctagaaaagg tacgaagcag 1320 tcaccgtcac tatgcattag agtaaataat agggagttat tttttgtagc ttcagaaagt 1380 agctataatg aaagtgatat taatacacct aaagaaattg acgatacaac aaatctaaat 1440 aataattata gaaataattt agatgaagtt attttagatt ataatagtga gacaatacct 1500 caaatatcaa atcgaacatt aaatacactt gtacaagaca atagttatgt gccaagatat 1560 gattctaatg gaacaagtga aatagaggaa tatgatgttg ttgactttaa tgtatttttc 1620 tatttacatg cacaaaaagt accagaaggt gaaaccaata taagtttaac ttcttcaatt 1680 gatacagcat tattagaaga atccaaagta tatacatttt tttcttcaga gtttatcgat 1740 actatcaata aacctgtaaa tgcagcacta tttatagatt ggataagcaa agtaataaga 1800 gattttacca ctgaagctac acaaaaaagt actgttgata agattgcaga catatcttta 1860 attgtaccct atgtaggtct tgctttgaat atagttattg aggcagaaaa aggaaatttt 1920 gaggaggcat ttgaattatt aggagcgggt attttattag aatttgtgcc agagcttaca 1980 attcctgtaa ttttagtgtt tacgataaaa tcctatatag attcatatga gaataaaaat 2040 aaagcaatta aagcaataaa taattcatta atcgaaagag aagcaaagtg gaaagaaata 2100 tatagttgga tagtatcaaa ttggcttact agaattaata cgcaatttaa taaaagaaaa 2160 gagcaaatgt atcaggcttt acaaaatcaa gtagatgcaa taaaaacagc aatagaatat 2220 aaatataata attatacttc agatgagaaa aatagacttg aatctaaata taatatcaat 2280 aatatagaag aagaattgaa taaaaaagtt tctttagcaa tgaaaaatat agaaagattt 2340 atgacagaaa gttctatatc ttatttaatg aaattaataa atgaagccga agttggtaaa 2400 ttaaaagaat atgataaaca tgttaagagc gatttattag actatattct ctaccataaa 2460 ttaatcttag gagagcagac aaaggaatta attgatttgg tgactagtac tttgaatagt 2520 agtattccat ttgaactttc ttcatatact aatgataaaa ttctaattat atattttaat 2580 agattatata aaaaaattaa agatagttct attttagata tgcgatatga aaataataaa 2640 tttatagata tctctggata tggttcaaat ataagcatta atggaaacgt atatatttat 2700 tcaacaaata gaaatcaatt tggaatatat agtggtaggc ttagtgaagt taatatagct 2760 caaaataatg atattatata caatagtaga tatcaaaatt ttagtattag tttctgggta 2820 accattccta aacactacag acctatgaat cgtaatcggg aatacactat aataaattgt 2880 atggggaata ataattcggg atggaaaata tcacttagaa ctattagaga ttgtgaaata 2940 atttggactt tacaagatac ttccggaaat aaggaaaaat taatttttag gtatgaagaa 3000 cttgctagta tatctgatta tataaataaa tggatttttg taactattac taataataga 3060 ttaggcaatt ctagaattta catcaatgga aatttaatag ttgaaaaatc aatttcgaat 3120 ttaggtgata ttcatgttag tgataatata ttatttaaaa ttgttggttg tgatgatgaa 3180 acgtatgttg gtataagata ttttaaagtt tttaatacgg aattagataa aacagaaatt 3240 gagactttat atagtaatga gccagatcca agtatcttaa aagactattg gggaaattat 3300 ttgctatata ataaaaaata ttatttattc aatttactaa gaaaagataa gtatattact 3360 cggaattcag gcattttaaa tattaatcaa caaagaggtg ttactggagg catatctgtt 3420 tttttgaact ataaattata tgaaggagta gaagttatta taagaaaaaa tgctcctata 3480 gatatatcta atacagataa ttttgttaga aaaaacgatc tagcatacat taatgtagta 3540 gatcatggtg tagaatatcg gttatatgct gatatatcaa ttacaaaatc agagaaaata 3600 ataaaattaa taagaacatc taatccaaac gatagcttag gtcaaattat agttatggat 3660 tcaataggaa ataattgcac aatgaatttt caaaacaatg atgggagcaa tataggatta 3720 ctaggttttc attcagatga tttggttgct agtagttggt attataacca tatacgaaga 3780 aacactagca gtaatggatg cttttggagt tttatttcta aagagcatgg ttggaaagaa 3840 taa 3843 <210> 12 <211> 3604 <212> PRT <213> Clostridium botulinum <400> 12 Met Glu Thr Pro Arg Val Ala Leu Val Ala Leu Ile Leu Glu Ala Ser 1 5 10 15 Asn Ser Glu Arg Pro His Glu Ala Ser Asn Thr Tyr Arg Ala Ser Asn 20 25 30 Ala Ser Pro Pro Arg Val Ala Leu Ala Ser Asn Ala Ser Pro Gly Leu 35 40 45 Thr His Arg Ile Leu Glu Leu Glu Thr Tyr Arg Met Glu Thr Gly Leu 50 55 60 Asn Leu Tyr Ser Pro Arg Thr Tyr Arg Gly Leu Gly Leu Ala Arg Gly 65 70 75 80 Ser Glu Arg Ala Arg Gly Leu Tyr Ser Thr Tyr Arg Thr Tyr Arg Leu 85 90 95 Tyr Ser Ala Leu Ala Pro His Glu Gly Leu Ile Leu Glu Met Glu Thr 100 105 110 Pro Arg Ala Ser Asn Val Ala Leu Thr Arg Pro Ile Leu Glu Met Glu 115 120 125 Thr Pro Arg Gly Leu Ala Arg Gly Ala Ser Pro Thr His Arg Ile Leu 130 135 140 Glu Gly Leu Tyr Thr His Arg Leu Tyr Ser Pro Arg Ala Ser Pro Gly 145 150 155 160 Leu Pro His Glu Gly Leu Asn Val Ala Leu Pro Arg Ala Ser Pro Ser 165 170 175 Glu Arg Leu Glu Leu Tyr Ser Ala Ser Asn Gly Leu Tyr Ser Glu Arg 180 185 190 Ser Glu Arg Ala Leu Ala Thr Tyr Arg Thr Tyr Arg Ala Ser Pro Pro 195 200 205 Arg Ala Ser Asn Thr Tyr Arg Leu Glu Thr His Arg Thr His Arg Ala 210 215 220 Ser Pro Ala Leu Ala Gly Leu Leu Tyr Ser Ala Ser Pro Ala Arg Gly 225 230 235 240 Thr Tyr Arg Leu Glu Leu Tyr Ser Thr His Arg Met Glu Thr Ile Leu 245 250 255 Glu Leu Tyr Ser Leu Glu Pro His Glu Ala Ser Asn Ala Arg Gly Ile 260 265 270 Leu Glu Ala Ser Asn Ser Glu Arg Ala Ser Asn Pro Arg Thr His Arg 275 280 285 Gly Leu Tyr Leu Tyr Ser Val Ala Leu Leu Glu Leu Glu Gly Leu Gly 290 295 300 Leu Val Ala Leu Ser Glu Arg Ala Ser Asn Ala Leu Ala Ala Arg Gly 305 310 315 320 Pro Arg Thr Tyr Arg Leu Glu Gly Leu Tyr Ala Ser Pro Ala Ser Pro 325 330 335 Ala Ser Pro Thr His Arg Leu Glu Ile Leu Glu Ala Ser Asn Gly Leu 340 345 350 Pro His Glu Leu Glu Pro Arg Val Ala Leu Ala Ser Asn Val Ala Leu 355 360 365 Thr His Arg Thr His Arg Ser Glu Arg Val Ala Leu Ala Ser Asn Ile 370 375 380 Leu Glu Leu Tyr Ser Pro His Glu Ser Glu Arg Thr His Arg Ala Ser 385 390 395 400 Pro Val Ala Leu Gly Leu Ser Glu Arg Ser Glu Arg Ile Leu Glu Ile 405 410 415 Leu Glu Ser Glu Arg Ala Ser Asn Leu Glu Leu Glu Val Ala Leu Leu 420 425 430 Glu Gly Leu Tyr Ala Leu Ala Gly Leu Tyr Pro Arg Ala Ser Pro Ile 435 440 445 Leu Glu Pro His Glu Leu Tyr Ser Ala Leu Ala Thr Tyr Arg Cys Tyr 450 455 460 Ser Thr His Arg Pro Arg Leu Glu Val Ala Leu Ala Arg Gly Pro His 465 470 475 480 Glu Ala Ser Asn Leu Tyr Ser Ser Glu Arg Ala Ser Pro Leu Tyr Ser 485 490 495 Leu Glu Ile Leu Glu Gly Leu Pro Arg Ser Glu Arg Ala Ser Asn His 500 505 510 Ile Ser Gly Leu Tyr Pro His Glu Gly Leu Tyr Ser Glu Arg Ile Leu 515 520 525 Glu Ala Ser Asn Ile Leu Glu Leu Glu Thr His Arg Pro His Glu Ser 530 535 540 Glu Arg Pro Arg Gly Leu Thr Tyr Arg Gly Leu His Ile Ser Ile Leu 545 550 555 560 Glu Pro His Glu Ala Ser Asn Ala Ser Pro Ile Leu Glu Ser Glu Arg 565 570 575 Gly Leu Tyr Gly Leu Tyr Ala Ser Asn His Ile Ser Ala Ser Asn Ser 580 585 590 Glu Arg Thr His Arg Gly Leu Ser Glu Arg Pro His Glu Ile Leu Glu 595 600 605 Ala Leu Ala Ala Ser Pro Pro Arg Ala Leu Ala Ile Leu Glu Ser Glu 610 615 620 Arg Leu Glu Ala Leu Ala His Ile Ser Gly Leu Leu Glu Ile Leu Glu 625 630 635 640 His Ile Ser Ala Leu Ala Leu Glu His Ile Ser Gly Leu Tyr Leu Glu 645 650 655 Thr Tyr Arg Gly Leu Tyr Ala Leu Ala Leu Tyr Ser Ala Leu Ala Val 660 665 670 Ala Leu Thr His Arg His Ile Ser Leu Tyr Ser Gly Leu Ser Glu Arg 675 680 685 Leu Glu Val Ala Leu Ala Leu Ala Gly Leu Ala Arg Gly Gly Leu Tyr 690 695 700 Pro Arg Leu Glu Met Glu Thr Ile Leu Glu Ala Leu Ala Gly Leu Leu 705 710 715 720 Tyr Ser Pro Arg Ile Leu Glu Ala Arg Gly Leu Glu Gly Leu Gly Leu 725 730 735 Pro His Glu Leu Glu Thr His Arg Pro His Glu Gly Leu Tyr Gly Leu 740 745 750 Tyr Gly Leu Ala Ser Pro Leu Glu Ala Ser Asn Ile Leu Glu Ile Leu 755 760 765 Glu Pro Arg Ser Glu Arg Ala Leu Ala Met Glu Thr Leu Tyr Ser Gly 770 775 780 Leu Leu Tyr Ser Ile Leu Glu Thr Tyr Arg Ala Ser Asn Ala Ser Pro 785 790 795 800 Leu Glu Leu Glu Ala Leu Ala Ala Ser Asn Thr Tyr Arg Gly Leu Leu 805 810 815 Tyr Ser Ile Leu Glu Ala Leu Ala Thr His Arg Ala Arg Gly Leu Glu 820 825 830 Ala Arg Gly Gly Leu Val Ala Leu Ala Ser Asn Thr His Arg Ala Leu 835 840 845 Ala Pro Arg Pro Arg Gly Leu Tyr Thr Tyr Arg Ala Ser Pro Ile Leu 850 855 860 Glu Ala Ser Asn Gly Leu Thr Tyr Arg Leu Tyr Ser Ala Ser Pro Thr 865 870 875 880 Tyr Arg Pro His Glu Gly Leu Asn Thr Arg Pro Leu Tyr Ser Thr Tyr 885 890 895 Arg Gly Leu Tyr Leu Glu Ala Ser Pro Ala Arg Gly Ala Ser Asn Ala 900 905 910 Leu Ala Ala Ser Pro Gly Leu Tyr Ser Glu Arg Thr Tyr Arg Thr His 915 920 925 Arg Val Ala Leu Ala Ser Asn Ala Arg Gly Ala Ser Asn Leu Tyr Ser 930 935 940 Pro His Glu Ala Ser Asn Gly Leu Ile Leu Glu Thr Tyr Arg Leu Tyr 945 950 955 960 Ser Leu Tyr Ser Leu Glu Thr Tyr Arg Ser Glu Arg Pro His Glu Thr 965 970 975 His Arg Gly Leu Ile Leu Glu Ala Ser Pro Leu Glu Ala Leu Ala Ala 980 985 990 Ser Asn Leu Tyr Ser Pro His Glu Leu Tyr Ser Val Ala Leu Leu Tyr 995 1000 1005 Ser Cys Tyr Ser Ala Arg Gly Ala Ser Asn Thr His Arg Thr Tyr Arg 1010 1015 1020 Pro His Glu Ile Leu Glu Leu Tyr Ser Thr Tyr Arg Gly Leu Tyr Pro 1025 1030 1035 1040 His Glu Val Ala Leu Leu Tyr Ser Val Ala Leu Pro Arg Ala Ser Asn 1045 1050 1055 Leu Glu Leu Glu Ala Ser Pro Ala Ser Pro Ala Ser Pro Ile Leu Glu 1060 1065 1070 Thr Tyr Arg Thr His Arg Val Ala Leu Ser Glu Arg Gly Leu Gly Leu 1075 1080 1085 Tyr Pro His Glu Ala Ser Asn Ile Leu Glu Gly Leu Tyr Ala Ser Asn 1090 1095 1100 Leu Glu Ala Leu Ala Val Ala Leu Ala Ser Asn Ala Ser Asn Ala Arg 1105 1110 1115 1120 Gly Gly Leu Tyr Gly Leu Asn Ala Ser Asn Ile Leu Glu Ala Ser Asn 1125 1130 1135 Leu Glu Ala Ser Asn Pro Arg Leu Tyr Ser Ile Leu Glu Ile Leu Glu 1140 1145 1150 Ala Ser Pro Ser Glu Arg Ile Leu Glu Pro Arg Ala Ser Pro Leu Tyr 1155 1160 1165 Ser Gly Leu Tyr Leu Glu Val Ala Leu Gly Leu Leu Tyr Ser Ile Leu 1170 1175 1180 Glu Ile Leu Glu Leu Tyr Ser Pro His Glu Cys Tyr Ser Leu Tyr Ser 1185 1190 1195 1200 Ser Glu Arg Ile Leu Glu Ile Leu Glu Pro Arg Ala Arg Gly Leu Tyr 1205 1210 1215 Ser Gly Leu Tyr Thr His Arg Leu Tyr Ser Gly Leu Asn Ser Glu Arg 1220 1225 1230 Pro Arg Ser Glu Arg Leu Glu Cys Tyr Ser Ile Leu Glu Ala Arg Gly 1235 1240 1245 Val Ala Leu Ala Ser Asn Ala Ser Asn Ala Arg Gly Gly Leu Leu Glu 1250 1255 1260 Pro His Glu Pro His Glu Val Ala Leu Ala Leu Ala Ser Glu Arg Gly 1265 1270 1275 1280 Leu Ser Glu Arg Ser Glu Arg Thr Tyr Arg Ala Ser Asn Gly Leu Ser 1285 1290 1295 Glu Arg Ala Ser Pro Ile Leu Glu Ala Ser Asn Thr His Arg Pro Arg 1300 1305 1310 Leu Tyr Ser Gly Leu Ile Leu Glu Ala Ser Pro Ala Ser Pro Thr His 1315 1320 1325 Arg Thr His Arg Ala Ser Asn Leu Glu Ala Ser Asn Ala Ser Asn Ala 1330 1335 1340 Ser Asn Thr Tyr Arg Ala Arg Gly Ala Ser Asn Ala Ser Asn Leu Glu 1345 1350 1355 1360 Ala Ser Pro Gly Leu Val Ala Leu Ile Leu Glu Leu Glu Ala Ser Pro 1365 1370 1375 Thr Tyr Arg Ala Ser Asn Ser Glu Arg Gly Leu Thr His Arg Ile Leu 1380 1385 1390 Glu Pro Arg Gly Leu Asn Ile Leu Glu Ser Glu Arg Ala Ser Asn Ala 1395 1400 1405 Arg Gly Thr His Arg Leu Glu Ala Ser Asn Thr His Arg Leu Glu Val 1410 1415 1420 Ala Leu Gly Leu Asn Ala Ser Pro Ala Ser Asn Ser Glu Arg Thr Tyr 1425 1430 1435 1440 Arg Val Ala Leu Pro Arg Ala Arg Gly Thr Tyr Arg Ala Ser Pro Ser 1445 1450 1455 Glu Arg Ala Ser Asn Gly Leu Tyr Thr His Arg Ser Glu Arg Gly Leu 1460 1465 1470 Ile Leu Glu Gly Leu Gly Leu Thr Tyr Arg Ala Ser Pro Val Ala Leu 1475 1480 1485 Val Ala Leu Ala Ser Pro Pro His Glu Ala Ser Asn Val Ala Leu Pro 1490 1495 1500 His Glu Pro His Glu Thr Tyr Arg Leu Glu His Ile Ser Ala Leu Ala 1505 1510 1515 1520 Gly Leu Asn Leu Tyr Ser Val Ala Leu Pro Arg Gly Leu Gly Leu Tyr 1525 1530 1535 Gly Leu Thr His Arg Ala Ser Asn Ile Leu Glu Ser Glu Arg Leu Glu 1540 1545 1550 Thr His Arg Ser Glu Arg Ser Glu Arg Ile Leu Glu Ala Ser Pro Thr 1555 1560 1565 His Arg Ala Leu Ala Leu Glu Leu Glu Gly Leu Gly Leu Ser Glu Arg 1570 1575 1580 Leu Tyr Ser Val Ala Leu Thr Tyr Arg Thr His Arg Pro His Glu Pro 1585 1590 1595 1600 His Glu Ser Glu Arg Ser Glu Arg Gly Leu Pro His Glu Ile Leu Glu 1605 1610 1615 Ala Ser Pro Thr His Arg Ile Leu Glu Ala Ser Asn Leu Tyr Ser Pro 1620 1625 1630 Arg Val Ala Leu Ala Ser Asn Ala Leu Ala Ala Leu Ala Leu Glu Pro 1635 1640 1645 His Glu Ile Leu Glu Ala Ser Pro Thr Arg Pro Ile Leu Glu Ser Glu 1650 1655 1660 Arg Leu Tyr Ser Val Ala Leu Ile Leu Glu Ala Arg Gly Ala Ser Pro 1665 1670 1675 1680 Pro His Glu Thr His Arg Thr His Arg Gly Leu Ala Leu Ala Thr His 1685 1690 1695 Arg Gly Leu Asn Leu Tyr Ser Ser Glu Arg Thr His Arg Val Ala Leu 1700 1705 1710 Ala Ser Pro Leu Tyr Ser Ile Leu Glu Ala Leu Ala Ala Ser Pro Ile 1715 1720 1725 Leu Glu Ser Glu Arg Leu Glu Ile Leu Glu Val Ala Leu Pro Arg Thr 1730 1735 1740 Tyr Arg Val Ala Leu Gly Leu Tyr Leu Glu Ala Leu Ala Leu Glu Ala 1745 1750 1755 1760 Ser Asn Ile Leu Glu Val Ala Leu Ile Leu Glu Gly Leu Ala Leu Ala 1765 1770 1775 Gly Leu Leu Tyr Ser Gly Leu Tyr Ala Ser Asn Pro His Glu Gly Leu 1780 1785 1790 Gly Leu Ala Leu Ala Pro His Glu Gly Leu Leu Glu Leu Glu Gly Leu 1795 1800 1805 Tyr Ala Leu Ala Gly Leu Tyr Ile Leu Glu Leu Glu Leu Glu Gly Leu 1810 1815 1820 Pro His Glu Val Ala Leu Pro Arg Gly Leu Leu Glu Thr His Arg Ile 1825 1830 1835 1840 Leu Glu Pro Arg Val Ala Leu Ile Leu Glu Leu Glu Val Ala Leu Pro 1845 1850 1855 His Glu Thr His Arg Ile Leu Glu Leu Tyr Ser Ser Glu Arg Thr Tyr 1860 1865 1870 Arg Ile Leu Glu Ala Ser Pro Ser Glu Arg Thr Tyr Arg Gly Leu Ala 1875 1880 1885 Ser Asn Leu Tyr Ser Ala Ser Asn Leu Tyr Ser Ala Leu Ala Ile Leu 1890 1895 1900 Glu Leu Tyr Ser Ala Leu Ala Ile Leu Glu Ala Ser Asn Ala Ser Asn 1905 1910 1915 1920 Ser Glu Arg Leu Glu Ile Leu Glu Gly Leu Ala Arg Gly Gly Leu Ala 1925 1930 1935 Leu Ala Leu Tyr Ser Thr Arg Pro Leu Tyr Ser Gly Leu Ile Leu Glu 1940 1945 1950 Thr Tyr Arg Ser Glu Arg Thr Arg Pro Ile Leu Glu Val Ala Leu Ser 1955 1960 1965 Glu Arg Ala Ser Asn Thr Arg Pro Leu Glu Thr His Arg Ala Arg Gly 1970 1975 1980 Ile Leu Glu Ala Ser Asn Thr His Arg Gly Leu Asn Pro His Glu Ala 1985 1990 1995 2000 Ser Asn Leu Tyr Ser Ala Arg Gly Leu Tyr Ser Gly Leu Gly Leu Asn 2005 2010 2015 Met Glu Thr Thr Tyr Arg Gly Leu Asn Ala Leu Ala Leu Glu Gly Leu 2020 2025 2030 Asn Ala Ser Asn Gly Leu Asn Val Ala Leu Ala Ser Pro Ala Leu Ala 2035 2040 2045 Ile Leu Glu Leu Tyr Ser Thr His Arg Ala Leu Ala Ile Leu Glu Gly 2050 2055 2060 Leu Thr Tyr Arg Leu Tyr Ser Thr Tyr Arg Ala Ser Asn Ala Ser Asn 2065 2070 2075 2080 Thr Tyr Arg Thr His Arg Ser Glu Arg Ala Ser Pro Gly Leu Leu Tyr 2085 2090 2095 Ser Ala Ser Asn Ala Arg Gly Leu Glu Gly Leu Ser Glu Arg Leu Tyr 2100 2105 2110 Ser Thr Tyr Arg Ala Ser Asn Ile Leu Glu Ala Ser Asn Ala Ser Asn 2115 2120 2125 Ile Leu Glu Gly Leu Gly Leu Gly Leu Leu Glu Ala Ser Asn Leu Tyr 2130 2135 2140 Ser Leu Tyr Ser Val Ala Leu Ser Glu Arg Leu Glu Ala Leu Ala Met 2145 2150 2155 2160 Glu Thr Leu Tyr Ser Ala Ser Asn Ile Leu Glu Gly Leu Ala Arg Gly 2165 2170 2175 Pro His Glu Met Glu Thr Thr His Arg Gly Leu Ser Glu Arg Ser Glu 2180 2185 2190 Arg Ile Leu Glu Ser Glu Arg Thr Tyr Arg Leu Glu Met Glu Thr Leu 2195 2200 2205 Tyr Ser Leu Glu Ile Leu Glu Ala Ser Asn Gly Leu Ala Leu Ala Gly 2210 2215 2220 Leu Val Ala Leu Gly Leu Tyr Leu Tyr Ser Leu Glu Leu Tyr Ser Gly 2225 2230 2235 2240 Leu Thr Tyr Arg Ala Ser Pro Leu Tyr Ser His Ile Ser Val Ala Leu 2245 2250 2255 Leu Tyr Ser Ser Glu Arg Ala Ser Pro Leu Glu Leu Glu Ala Ser Pro 2260 2265 2270 Thr Tyr Arg Ile Leu Glu Leu Glu Thr Tyr Arg His Ile Ser Leu Tyr 2275 2280 2285 Ser Leu Glu Ile Leu Glu Leu Glu Gly Leu Tyr Gly Leu Gly Leu Asn 2290 2295 2300 Thr His Arg Leu Tyr Ser Gly Leu Leu Glu Ile Leu Glu Ala Ser Pro 2305 2310 2315 2320 Leu Glu Val Ala Leu Thr His Arg Ser Glu Arg Thr His Arg Leu Glu 2325 2330 2335 Ala Ser Asn Ser Glu Arg Ser Glu Arg Ile Leu Glu Pro Arg Pro His 2340 2345 2350 Glu Gly Leu Leu Glu Ser Glu Arg Ser Glu Arg Thr Tyr Arg Thr His 2355 2360 2365 Arg Ala Ser Asn Ala Ser Pro Leu Tyr Ser Ile Leu Glu Leu Glu Ile 2370 2375 2380 Leu Glu Ile Leu Glu Thr Tyr Arg Pro His Glu Ala Ser Asn Ala Arg 2385 2390 2395 2400 Gly Leu Glu Thr Tyr Arg Leu Tyr Ser Leu Tyr Ser Ile Leu Glu Leu 2405 2410 2415 Tyr Ser Ala Ser Pro Ser Glu Arg Ser Glu Arg Ile Leu Glu Leu Glu 2420 2425 2430 Ala Ser Pro Met Glu Thr Ala Arg Gly Thr Tyr Arg Gly Leu Ala Ser 2435 2440 2445 Asn Ala Ser Asn Leu Tyr Ser Pro His Glu Ile Leu Glu Ala Ser Pro 2450 2455 2460 Ile Leu Glu Ser Glu Arg Gly Leu Tyr Thr Tyr Arg Gly Leu Tyr Ser 2465 2470 2475 2480 Glu Arg Ala Ser Asn Ile Leu Glu Ser Glu Arg Ile Leu Glu Ala Ser 2485 2490 2495 Asn Gly Leu Tyr Ala Ser Asn Val Ala Leu Thr Tyr Arg Ile Leu Glu 2500 2505 2510 Thr Tyr Arg Ser Glu Arg Thr His Arg Ala Ser Asn Ala Arg Gly Ala 2515 2520 2525 Ser Asn Gly Leu Asn Pro His Glu Gly Leu Tyr Ile Leu Glu Thr Tyr 2530 2535 2540 Arg Ser Glu Arg Gly Leu Tyr Ala Arg Gly Leu Glu Ser Glu Arg Gly 2545 2550 2555 2560 Leu Val Ala Leu Ala Ser Asn Ile Leu Glu Ala Leu Ala Gly Leu Asn 2565 2570 2575 Ala Ser Asn Ala Ser Asn Ala Ser Pro Ile Leu Glu Ile Leu Glu Thr 2580 2585 2590 Tyr Arg Ala Ser Asn Ser Glu Arg Ala Arg Gly Thr Tyr Arg Gly Leu 2595 2600 2605 Asn Ala Ser Asn Pro His Glu Ser Glu Arg Ile Leu Glu Ser Glu Arg 2610 2615 2620 Pro His Glu Thr Arg Pro Val Ala Leu Thr His Arg Ile Leu Glu Pro 2625 2630 2635 2640 Arg Leu Tyr Ser His Ile Ser Thr Tyr Arg Ala Arg Gly Pro Arg Met 2645 2650 2655 Glu Thr Ala Ser Asn Ala Arg Gly Ala Ser Asn Ala Arg Gly Gly Leu 2660 2665 2670 Thr Tyr Arg Thr His Arg Ile Leu Glu Ile Leu Glu Ala Ser Asn Cys 2675 2680 2685 Tyr Ser Met Glu Thr Gly Leu Tyr Ala Ser Asn Ala Ser Asn Ala Ser 2690 2695 2700 Asn Ser Glu Arg Gly Leu Tyr Thr Arg Pro Leu Tyr Ser Ile Leu Glu 2705 2710 2715 2720 Ser Glu Arg Leu Glu Ala Arg Gly Thr His Arg Ile Leu Glu Ala Arg 2725 2730 2735 Gly Ala Ser Pro Cys Tyr Ser Gly Leu Ile Leu Glu Ile Leu Glu Thr 2740 2745 2750 Arg Pro Thr His Arg Leu Glu Gly Leu Asn Ala Ser Pro Thr His Arg 2755 2760 2765 Ser Glu Arg Gly Leu Tyr Ala Ser Asn Leu Tyr Ser Gly Leu Leu Tyr 2770 2775 2780 Ser Leu Glu Ile Leu Glu Pro His Glu Ala Arg Gly Thr Tyr Arg Gly 2785 2790 2795 2800 Leu Gly Leu Leu Glu Ala Leu Ala Ser Glu Arg Ile Leu Glu Ser Glu 2805 2810 2815 Arg Ala Ser Pro Thr Tyr Arg Ile Leu Glu Ala Ser Asn Leu Tyr Ser 2820 2825 2830 Thr Arg Pro Ile Leu Glu Pro His Glu Val Ala Leu Thr His Arg Ile 2835 2840 2845 Leu Glu Thr His Arg Ala Ser Asn Ala Ser Asn Ala Arg Gly Leu Glu 2850 2855 2860 Gly Leu Tyr Ala Ser Asn Ser Glu Arg Ala Arg Gly Ile Leu Glu Thr 2865 2870 2875 2880 Tyr Arg Ile Leu Glu Ala Ser Asn Gly Leu Tyr Ala Ser Asn Leu Glu 2885 2890 2895 Ile Leu Glu Val Ala Leu Gly Leu Leu Tyr Ser Ser Glu Arg Ile Leu 2900 2905 2910 Glu Ser Glu Arg Ala Ser Asn Leu Glu Gly Leu Tyr Ala Ser Pro Ile 2915 2920 2925 Leu Glu His Ile Ser Val Ala Leu Ser Glu Arg Ala Ser Pro Ala Ser 2930 2935 2940 Asn Ile Leu Glu Leu Glu Pro His Glu Leu Tyr Ser Ile Leu Glu Val 2945 2950 2955 2960 Ala Leu Gly Leu Tyr Cys Tyr Ser Ala Ser Pro Ala Ser Pro Gly Leu 2965 2970 2975 Thr His Arg Thr Tyr Arg Val Ala Leu Gly Leu Tyr Ile Leu Glu Ala 2980 2985 2990 Arg Gly Thr Tyr Arg Pro His Glu Leu Tyr Ser Val Ala Leu Pro His 2995 3000 3005 Glu Ala Ser Asn Thr His Arg Gly Leu Leu Glu Ala Ser Pro Leu Tyr 3010 3015 3020 Ser Thr His Arg Gly Leu Ile Leu Glu Gly Leu Thr His Arg Leu Glu 3025 3030 3035 3040 Thr Tyr Arg Ser Glu Arg Ala Ser Asn Gly Leu Pro Arg Ala Ser Pro 3045 3050 3055 Pro Arg Ser Glu Arg Ile Leu Glu Leu Glu Leu Tyr Ser Ala Ser Pro 3060 3065 3070 Thr Tyr Arg Thr Arg Pro Gly Leu Tyr Ala Ser Asn Thr Tyr Arg Leu 3075 3080 3085 Glu Leu Glu Thr Tyr Arg Ala Ser Asn Leu Tyr Ser Leu Tyr Ser Thr 3090 3095 3100 Tyr Arg Thr Tyr Arg Leu Glu Pro His Glu Ala Ser Asn Leu Glu Leu 3105 3110 3115 3120 Glu Ala Arg Gly Leu Tyr Ser Ala Ser Pro Leu Tyr Ser Thr Tyr Arg 3125 3130 3135 Ile Leu Glu Thr His Arg Ala Arg Gly Ala Ser Asn Ser Glu Arg Gly 3140 3145 3150 Leu Tyr Ile Leu Glu Leu Glu Ala Ser Asn Ile Leu Glu Ala Ser Asn 3155 3160 3165 Gly Leu Asn Gly Leu Asn Ala Arg Gly Gly Leu Tyr Val Ala Leu Thr 3170 3175 3180 His Arg Gly Leu Tyr Gly Leu Tyr Ile Leu Glu Ser Glu Arg Val Ala 3185 3190 3195 3200 Leu Pro His Glu Leu Glu Ala Ser Asn Thr Tyr Arg Leu Tyr Ser Leu 3205 3210 3215 Glu Thr Tyr Arg Gly Leu Gly Leu Tyr Val Ala Leu Gly Leu Val Ala 3220 3225 3230 Leu Ile Leu Glu Ile Leu Glu Ala Arg Gly Leu Tyr Ser Ala Ser Asn 3235 3240 3245 Ala Leu Ala Pro Arg Ile Leu Glu Ala Ser Pro Ile Leu Glu Ser Glu 3250 3255 3260 Arg Ala Ser Asn Thr His Arg Ala Ser Pro Ala Ser Asn Pro His Glu 3265 3270 3275 3280 Val Ala Leu Ala Arg Gly Leu Tyr Ser Ala Ser Asn Ala Ser Pro Leu 3285 3290 3295 Glu Ala Leu Ala Thr Tyr Arg Ile Leu Glu Ala Ser Asn Val Ala Leu 3300 3305 3310 Val Ala Leu Ala Ser Pro His Ile Ser Gly Leu Tyr Val Ala Leu Gly 3315 3320 3325 Leu Thr Tyr Arg Ala Arg Gly Leu Glu Thr Tyr Arg Ala Leu Ala Ala 3330 3335 3340 Ser Pro Ile Leu Glu Ser Glu Arg Ile Leu Glu Thr His Arg Leu Tyr 3345 3350 3355 3360 Ser Ser Glu Arg Gly Leu Leu Tyr Ser Ile Leu Glu Ile Leu Glu Leu 3365 3370 3375 Tyr Ser Leu Glu Ile Leu Glu Ala Arg Gly Thr His Arg Ser Glu Arg 3380 3385 3390 Ala Ser Asn Pro Arg Ala Ser Asn Ala Ser Pro Ser Glu Arg Leu Glu 3395 3400 3405 Gly Leu Tyr Gly Leu Asn Ile Leu Glu Ile Leu Glu Val Ala Leu Met 3410 3415 3420 Glu Thr Ala Ser Pro Ser Glu Arg Ile Leu Glu Gly Leu Tyr Ala Ser 3425 3430 3435 3440 Asn Ala Ser Asn Cys Tyr Ser Thr His Arg Met Glu Thr Ala Ser Asn 3445 3450 3455 Pro His Glu Gly Leu Asn Ala Ser Asn Ala Ser Asn Ala Ser Pro Gly 3460 3465 3470 Leu Tyr Ser Glu Arg Ala Ser Asn Ile Leu Glu Gly Leu Tyr Leu Glu 3475 3480 3485 Leu Glu Gly Leu Tyr Pro His Glu His Ile Ser Ser Glu Arg Ala Ser 3490 3495 3500 Pro Ala Ser Pro Leu Glu Val Ala Leu Ala Leu Ala Ser Glu Arg Ser 3505 3510 3515 3520 Glu Arg Thr Arg Pro Thr Tyr Arg Thr Tyr Arg Ala Ser Asn His Ile 3525 3530 3535 Ser Ile Leu Glu Ala Arg Gly Ala Arg Gly Ala Ser Asn Thr His Arg 3540 3545 3550 Ser Glu Arg Ser Glu Arg Ala Ser Asn Gly Leu Tyr Cys Tyr Ser Pro 3555 3560 3565 His Glu Thr Arg Pro Ser Glu Arg Pro His Glu Ile Leu Glu Ser Glu 3570 3575 3580 Arg Leu Tyr Ser Gly Leu His Ile Ser Gly Leu Tyr Thr Arg Pro Leu 3585 3590 3595 3600 Tyr Ser Gly Leu <210> 13 <211> 3894 <212> DNA <213> Clostridium botulinum <220> <221> misc_feature <222> (20) <223> n is a, c, g, or t <400> 13 atgccagtta atataaaaan ctttaattat aatgacccta ttaataatga tgacattatt 60 atgatggaac cattcaatga cccagggcca ggaacatatt ataaagcttt taggattata 120 gatcgtattt ggatagtacc agaaaggttt acttatggat ttcaacctga ccaatttaat 180 gccagtacag gagtttttag taaagatgtc tacgaatatt acgatccaac ttatttaaaa 240 accgatgctg aaaaagataa atttttaaaa acaatgatta aattatttaa tagaattaat 300 tcaaaaccat caggacagag attactggat atgatagtag atgctatacc ttatcttgga 360 aatgcatcta caccgcccga caaatttgca gcaaatgttg caaatgtatc tattaataaa 420 aaaattatcc aacctggagc tgaagatcaa ataaaaggtt taatgacaaa tttaataata 480 tttggaccag gaccagttct aagtgataat tttactgata gtatgattat gaatggccat 540 tccccaatat cagaaggatt tggtgcaaga atgatgataa gattttgtcc tagttgttta 600 aatgtattta ataatgttca ggaaaataaa gatacatcta tatttagtag acgcgcgtat 660 tttgcagatc cagctctaac gttaatgcat gaacttatac atgtgttaca tggattatat 720 ggaattaaga taagtaattt accaattact ccaaatacaa aagaattttt catgcaacat 780 agcgatcctg tacaagcaga agaactatat acattcggag gacatgatcc tagtgttata 840 agtccttcta cggatatgaa tatttataat aaagcgttac aaaattttca agatatagct 900 aataggctta atattgtttc aagtgcccaa gggagtggaa ttgatatttc cttatataaa 960 caaatatata aaaataaata tgattttgtt gaagatccta atggaaaata tagtgtagat 1020 aaggataagt ttgataaatt atataaggcc ttaatgtttg gctttactga aactaatcta 1080 gctggtgaat atggaataaa aactaggtat tcttatttta gtgaatattt gccaccgata 1140 aaaactgaaa aattgttaga caatacaatt tatactcaaa atgaaggctt taacatagct 1200 agtaaaaatc tcaaaacgga atttaatggt cagaataagg cggtaaataa agaggcttat 1260 gaagaaatca gcctagaaca tctcgttata tatagaatag caatgtgcaa gcctgtaatg 1320 tacaaaaata ccggtaaatc tgaacagtgt attattgtta ataatgagga tttatttttc 1380 atagctaata aagatagttt ttcaaaagat ttagctaaag cagaaactat agcatataat 1440 acacaaaata atactataga aaataatttt tctatagatc agttgatttt agataatgat 1500 ttaagcagtg gcatagactt accaaatgaa aacacagaac catttacaaa ttttgacgac 1560 atagatatcc ctgtgtatat taaacaatct gctttaaaaa aaatttttgt ggatggagat 1620 agcctttttg aatatttaca tgctcaaaca tttccttcta atatagaaaa tctacaacta 1680 acgaattcat taaatgatgc tttaagaaat aataataaag tctatacttt tttttctaca 1740 aaccttgttg aaaaagctaa tacagttgta ggtgcttcac tttttgtaaa ctgggtaaaa 1800 ggagtaatag atgattttac atctgaatcc acacaaaaaa gtactataga taaagtttca 1860 gatgtatcca taattattcc ctatatagga cctgctttga atgtaggaaa tgaaacagct 1920 aaagaaaatt ttaaaaatgc ttttgaaata ggtggagccg ctatcttaat ggagtttatt 1980 ccagaactta ttgtacctat agttggattt tttacattag aatcatatgt aggaaataaa 2040 gggcatatta ttatgacgat atccaatgct ttaaagaaaa gggatcaaaa atggacagat 2100 atgtatggtt tgatagtatc gcagtggctc tcaacggtta atactcaatt ttatacaata 2160 aaagaaagaa tgtacaatgc tttaaataat caatcacaag caatagaaaa aataatagaa 2220 gatcaatata atagatatag tgaagaagat aaaatgaata ttaacattga ttttaatgat 2280 atagatttta aacttaatca aagtataaat ttagcaataa acaatataga tgattttata 2340 aaccaatgtt ctatatcata tctaatgaat agaatgattc cattagctgt aaaaaagtta 2400 aaagactttg atgataatct taagagagat ttattggagt atatagatac aaatgaacta 2460 tatttacttg atgaagtaaa tattctaaaa tcaaaagtaa atagacacct aaaagacagt 2520 ataccatttg atctttcact atataccaag gacacaattt taatacaagt ttttaataat 2580 tatattagta atattagtag taatgctatt ttaagtttaa gttatagagg tgggcgttta 2640 atagattcat ctggatatgg tgcaactatg aatgtaggtt cagatgttat ctttaatgat 2700 ataggaaatg gtcaatttaa attaaataat tctgaaaata gtaatattac ggcacatcaa 2760 agtaaattcg ttgtatatga tagtatgttt gataatttta gcattaactt ttgggtaagg 2820 actcctaaat ataataataa tgatatacaa acttatcttc aaaatgagta tacaataatt 2880 agttgtataa aaaatgactc aggatggaaa gtatctatta agggaaatag aataatatgg 2940 acattaatag atgttaatgc aaaatctaaa tcaatatttt tcgaatatag tataaaagat 3000 aatatatcag attatataaa taaatggttt tccataacta ttactaatga tagattaggt 3060 aacgcaaata tttatataaa tggaagtttg aaaaaaagtg aaaaaatttt aaacttagat 3120 agaattaatt ctagtaatga tatagacttc aaattaatta attgtacaga tactactaaa 3180 tttgtttgga ttaaggattt taatattttt ggtagagaat taaatgctac agaagtatct 3240 tcactatatt ggattcaatc atctacaaat actttaaaag atttttgggg gaatccttta 3300 agatacgata cacaatacta tctgtttaat caaggtatgc aaaatatcta tataaagtat 3360 tttagtaaag cttctatggg ggaaactgca ccacgtacaa actttaataa tgcagcaata 3420 aattatcaaa atttatatct tggtttacga tttattataa aaaaagcatc aaattctcgg 3480 aatataaata atgataatat agtcagagaa ggagattata tatatcttaa tattgataat 3540 atttctgatg aatcttacag agtatatgtt ttggtgaatt ctaaagaaat tcaaactcaa 3600 ttatttttag cacccataaa tgatgatcct acgttctatg atgtactaca aataaaaaaa 3660 tattatgaaa aaacaacata taattgtcag atactttgcg aaaaagatac taaaacattt 3720 gggctgtttg gaattggtaa atttgttaaa gattatggat atgtttggga tacctatgat 3780 aattattttt gcataagtca gtggtatctc agaagaatat ctgaaaatat aaataaatta 3840 aggttgggat gtaattggca attcattccc gtggatgaag gatggacaga ataa 3894 <210> 14 <211> 3690 <212> PRT <213> Clostridium botulinum <220> <221> MISC_FEATURE <222> (18) <223> Xaa can be any naturally occurring amino acid <400> 14 Met Glu Thr Pro Arg Val Ala Leu Ala Ser Asn Ile Leu Glu Leu Tyr 1 5 10 15 Ser Xaa Ala Ala Pro His Glu Ala Ser Asn Thr Tyr Arg Ala Ser Asn 20 25 30 Ala Ser Pro Pro Arg Ile Leu Glu Ala Ser Asn Ala Ser Asn Ala Ser 35 40 45 Pro Ala Ser Pro Ile Leu Glu Ile Leu Glu Met Glu Thr Met Glu Thr 50 55 60 Gly Leu Pro Arg Pro His Glu Ala Ser Asn Ala Ser Pro Pro Arg Gly 65 70 75 80 Leu Tyr Pro Arg Gly Leu Tyr Thr His Arg Thr Tyr Arg Thr Tyr Arg 85 90 95 Leu Tyr Ser Ala Leu Ala Pro His Glu Ala Arg Gly Ile Leu Glu Ile 100 105 110 Leu Glu Ala Ser Pro Ala Arg Gly Ile Leu Glu Thr Arg Pro Ile Leu 115 120 125 Glu Val Ala Leu Pro Arg Gly Leu Ala Arg Gly Pro His Glu Thr His 130 135 140 Arg Thr Tyr Arg Gly Leu Tyr Pro His Glu Gly Leu Asn Pro Arg Ala 145 150 155 160 Ser Pro Gly Leu Asn Pro His Glu Ala Ser Asn Ala Leu Ala Ser Glu 165 170 175 Arg Thr His Arg Gly Leu Tyr Val Ala Leu Pro His Glu Ser Glu Arg 180 185 190 Leu Tyr Ser Ala Ser Pro Val Ala Leu Thr Tyr Arg Gly Leu Thr Tyr 195 200 205 Arg Thr Tyr Arg Ala Ser Pro Pro Arg Thr His Arg Thr Tyr Arg Leu 210 215 220 Glu Leu Tyr Ser Thr His Arg Ala Ser Pro Ala Leu Ala Gly Leu Leu 225 230 235 240 Tyr Ser Ala Ser Pro Leu Tyr Ser Pro His Glu Leu Glu Leu Tyr Ser 245 250 255 Thr His Arg Met Glu Thr Ile Leu Glu Leu Tyr Ser Leu Glu Pro His 260 265 270 Glu Ala Ser Asn Ala Arg Gly Ile Leu Glu Ala Ser Asn Ser Glu Arg 275 280 285 Leu Tyr Ser Pro Arg Ser Glu Arg Gly Leu Tyr Gly Leu Asn Ala Arg 290 295 300 Gly Leu Glu Leu Glu Ala Ser Pro Met Glu Thr Ile Leu Glu Val Ala 305 310 315 320 Leu Ala Ser Pro Ala Leu Ala Ile Leu Glu Pro Arg Thr Tyr Arg Leu 325 330 335 Glu Gly Leu Tyr Ala Ser Asn Ala Leu Ala Ser Glu Arg Thr His Arg 340 345 350 Pro Arg Pro Arg Ala Ser Pro Leu Tyr Ser Pro His Glu Ala Leu Ala 355 360 365 Ala Leu Ala Ala Ser Asn Val Ala Leu Ala Leu Ala Ala Ser Asn Val 370 375 380 Ala Leu Ser Glu Arg Ile Leu Glu Ala Ser Asn Leu Tyr Ser Leu Tyr 385 390 395 400 Ser Ile Leu Glu Ile Leu Glu Gly Leu Asn Pro Arg Gly Leu Tyr Ala 405 410 415 Leu Ala Gly Leu Ala Ser Pro Gly Leu Asn Ile Leu Glu Leu Tyr Ser 420 425 430 Gly Leu Tyr Leu Glu Met Glu Thr Thr His Arg Ala Ser Asn Leu Glu 435 440 445 Ile Leu Glu Ile Leu Glu Pro His Glu Gly Leu Tyr Pro Arg Gly Leu 450 455 460 Tyr Pro Arg Val Ala Leu Leu Glu Ser Glu Arg Ala Ser Pro Ala Ser 465 470 475 480 Asn Pro His Glu Thr His Arg Ala Ser Pro Ser Glu Arg Met Glu Thr 485 490 495 Ile Leu Glu Met Glu Thr Ala Ser Asn Gly Leu Tyr His Ile Ser Ser 500 505 510 Glu Arg Pro Arg Ile Leu Glu Ser Glu Arg Gly Leu Gly Leu Tyr Pro 515 520 525 His Glu Gly Leu Tyr Ala Leu Ala Ala Arg Gly Met Glu Thr Met Glu 530 535 540 Thr Ile Leu Glu Ala Arg Gly Pro His Glu Cys Tyr Ser Pro Arg Ser 545 550 555 560 Glu Arg Cys Tyr Ser Leu Glu Ala Ser Asn Val Ala Leu Pro His Glu 565 570 575 Ala Ser Asn Ala Ser Asn Val Ala Leu Gly Leu Asn Gly Leu Ala Ser 580 585 590 Asn Leu Tyr Ser Ala Ser Pro Thr His Arg Ser Glu Arg Ile Leu Glu 595 600 605 Pro His Glu Ser Glu Arg Ala Arg Gly Ala Arg Gly Ala Leu Ala Thr 610 615 620 Tyr Arg Pro His Glu Ala Leu Ala Ala Ser Pro Pro Arg Ala Leu Ala 625 630 635 640 Leu Glu Thr His Arg Leu Glu Met Glu Thr His Ile Ser Gly Leu Leu 645 650 655 Glu Ile Leu Glu His Ile Ser Val Ala Leu Leu Glu His Ile Ser Gly 660 665 670 Leu Tyr Leu Glu Thr Tyr Arg Gly Leu Tyr Ile Leu Glu Leu Tyr Ser 675 680 685 Ile Leu Glu Ser Glu Arg Ala Ser Asn Leu Glu Pro Arg Ile Leu Glu 690 695 700 Thr His Arg Pro Arg Ala Ser Asn Thr His Arg Leu Tyr Ser Gly Leu 705 710 715 720 Pro His Glu Pro His Glu Met Glu Thr Gly Leu Asn His Ile Ser Ser 725 730 735 Glu Arg Ala Ser Pro Pro Arg Val Ala Leu Gly Leu Asn Ala Leu Ala 740 745 750 Gly Leu Gly Leu Leu Glu Thr Tyr Arg Thr His Arg Pro His Glu Gly 755 760 765 Leu Tyr Gly Leu Tyr His Ile Ser Ala Ser Pro Pro Arg Ser Glu Arg 770 775 780 Val Ala Leu Ile Leu Glu Ser Glu Arg Pro Arg Ser Glu Arg Thr His 785 790 795 800 Arg Ala Ser Pro Met Glu Thr Ala Ser Asn Ile Leu Glu Thr Tyr Arg 805 810 815 Ala Ser Asn Leu Tyr Ser Ala Leu Ala Leu Glu Gly Leu Asn Ala Ser 820 825 830 Asn Pro His Glu Gly Leu Asn Ala Ser Pro Ile Leu Glu Ala Leu Ala 835 840 845 Ala Ser Asn Ala Arg Gly Leu Glu Ala Ser Asn Ile Leu Glu Val Ala 850 855 860 Leu Ser Glu Arg Ser Glu Arg Ala Leu Ala Gly Leu Asn Gly Leu Tyr 865 870 875 880 Ser Glu Arg Gly Leu Tyr Ile Leu Glu Ala Ser Pro Ile Leu Glu Ser 885 890 895 Glu Arg Leu Glu Thr Tyr Arg Leu Tyr Ser Gly Leu Asn Ile Leu Glu 900 905 910 Thr Tyr Arg Leu Tyr Ser Ala Ser Asn Leu Tyr Ser Thr Tyr Arg Ala 915 920 925 Ser Pro Pro His Glu Val Ala Leu Gly Leu Ala Ser Pro Pro Arg Ala 930 935 940 Ser Asn Gly Leu Tyr Leu Tyr Ser Thr Tyr Arg Ser Glu Arg Val Ala 945 950 955 960 Leu Ala Ser Pro Leu Tyr Ser Ala Ser Pro Leu Tyr Ser Pro His Glu 965 970 975 Ala Ser Pro Leu Tyr Ser Leu Glu Thr Tyr Arg Leu Tyr Ser Ala Leu 980 985 990 Ala Leu Glu Met Glu Thr Pro His Glu Gly Leu Tyr Pro His Glu Thr 995 1000 1005 His Arg Gly Leu Thr His Arg Ala Ser Asn Leu Glu Ala Leu Ala Gly 1010 1015 1020 Leu Tyr Gly Leu Thr Tyr Arg Gly Leu Tyr Ile Leu Glu Leu Tyr Ser 1025 1030 1035 1040 Thr His Arg Ala Arg Gly Thr Tyr Arg Ser Glu Arg Thr Tyr Arg Pro 1045 1050 1055 His Glu Ser Glu Arg Gly Leu Thr Tyr Arg Leu Glu Pro Arg Pro Arg 1060 1065 1070 Ile Leu Glu Leu Tyr Ser Thr His Arg Gly Leu Leu Tyr Ser Leu Glu 1075 1080 1085 Leu Glu Ala Ser Pro Ala Ser Asn Thr His Arg Ile Leu Glu Thr Tyr 1090 1095 1100 Arg Thr His Arg Gly Leu Asn Ala Ser Asn Gly Leu Gly Leu Tyr Pro 1105 1110 1115 1120 His Glu Ala Ser Asn Ile Leu Glu Ala Leu Ala Ser Glu Arg Leu Tyr 1125 1130 1135 Ser Ala Ser Asn Leu Glu Leu Tyr Ser Thr His Arg Gly Leu Pro His 1140 1145 1150 Glu Ala Ser Asn Gly Leu Tyr Gly Leu Asn Ala Ser Asn Leu Tyr Ser 1155 1160 1165 Ala Leu Ala Val Ala Leu Ala Ser Asn Leu Tyr Ser Gly Leu Ala Leu 1170 1175 1180 Ala Thr Tyr Arg Gly Leu Gly Leu Ile Leu Glu Ser Glu Arg Leu Glu 1185 1190 1195 1200 Gly Leu His Ile Ser Leu Glu Val Ala Leu Ile Leu Glu Thr Tyr Arg 1205 1210 1215 Ala Arg Gly Ile Leu Glu Ala Leu Ala Met Glu Thr Cys Tyr Ser Leu 1220 1225 1230 Tyr Ser Pro Arg Val Ala Leu Met Glu Thr Thr Tyr Arg Leu Tyr Ser 1235 1240 1245 Ala Ser Asn Thr His Arg Gly Leu Tyr Leu Tyr Ser Ser Glu Arg Gly 1250 1255 1260 Leu Gly Leu Asn Cys Tyr Ser Ile Leu Glu Ile Leu Glu Val Ala Leu 1265 1270 1275 1280 Ala Ser Asn Ala Ser Asn Gly Leu Ala Ser Pro Leu Glu Pro His Glu 1285 1290 1295 Pro His Glu Ile Leu Glu Ala Leu Ala Ala Ser Asn Leu Tyr Ser Ala 1300 1305 1310 Ser Pro Ser Glu Arg Pro His Glu Ser Glu Arg Leu Tyr Ser Ala Ser 1315 1320 1325 Pro Leu Glu Ala Leu Ala Leu Tyr Ser Ala Leu Ala Gly Leu Thr His 1330 1335 1340 Arg Ile Leu Glu Ala Leu Ala Thr Tyr Arg Ala Ser Asn Thr His Arg 1345 1350 1355 1360 Gly Leu Asn Ala Ser Asn Ala Ser Asn Thr His Arg Ile Leu Glu Gly 1365 1370 1375 Leu Ala Ser Asn Ala Ser Asn Pro His Glu Ser Glu Arg Ile Leu Glu 1380 1385 1390 Ala Ser Pro Gly Leu Asn Leu Glu Ile Leu Glu Leu Glu Ala Ser Pro 1395 1400 1405 Ala Ser Asn Ala Ser Pro Leu Glu Ser Glu Arg Ser Glu Arg Gly Leu 1410 1415 1420 Tyr Ile Leu Glu Ala Ser Pro Leu Glu Pro Arg Ala Ser Asn Gly Leu 1425 1430 1435 1440 Ala Ser Asn Thr His Arg Gly Leu Pro Arg Pro His Glu Thr His Arg 1445 1450 1455 Ala Ser Asn Pro His Glu Ala Ser Pro Ala Ser Pro Ile Leu Glu Ala 1460 1465 1470 Ser Pro Ile Leu Glu Pro Arg Val Ala Leu Thr Tyr Arg Ile Leu Glu 1475 1480 1485 Leu Tyr Ser Gly Leu Asn Ser Glu Arg Ala Leu Ala Leu Glu Leu Tyr 1490 1495 1500 Ser Leu Tyr Ser Ile Leu Glu Pro His Glu Val Ala Leu Ala Ser Pro 1505 1510 1515 1520 Gly Leu Tyr Ala Ser Pro Ser Glu Arg Leu Glu Pro His Glu Gly Leu 1525 1530 1535 Thr Tyr Arg Leu Glu His Ile Ser Ala Leu Ala Gly Leu Asn Thr His 1540 1545 1550 Arg Pro His Glu Pro Arg Ser Glu Arg Ala Ser Asn Ile Leu Glu Gly 1555 1560 1565 Leu Ala Ser Asn Leu Glu Gly Leu Asn Leu Glu Thr His Arg Ala Ser 1570 1575 1580 Asn Ser Glu Arg Leu Glu Ala Ser Asn Ala Ser Pro Ala Leu Ala Leu 1585 1590 1595 1600 Glu Ala Arg Gly Ala Ser Asn Ala Ser Asn Ala Ser Asn Leu Tyr Ser 1605 1610 1615 Val Ala Leu Thr Tyr Arg Thr His Arg Pro His Glu Pro His Glu Ser 1620 1625 1630 Glu Arg Thr His Arg Ala Ser Asn Leu Glu Val Ala Leu Gly Leu Leu 1635 1640 1645 Tyr Ser Ala Leu Ala Ala Ser Asn Thr His Arg Val Ala Leu Val Ala 1650 1655 1660 Leu Gly Leu Tyr Ala Leu Ala Ser Glu Arg Leu Glu Pro His Glu Val 1665 1670 1675 1680 Ala Leu Ala Ser Asn Thr Arg Pro Val Ala Leu Leu Tyr Ser Gly Leu 1685 1690 1695 Tyr Val Ala Leu Ile Leu Glu Ala Ser Pro Ala Ser Pro Pro His Glu 1700 1705 1710 Thr His Arg Ser Glu Arg Gly Leu Ser Glu Arg Thr His Arg Gly Leu 1715 1720 1725 Asn Leu Tyr Ser Ser Glu Arg Thr His Arg Ile Leu Glu Ala Ser Pro 1730 1735 1740 Leu Tyr Ser Val Ala Leu Ser Glu Arg Ala Ser Pro Val Ala Leu Ser 1745 1750 1755 1760 Glu Arg Ile Leu Glu Ile Leu Glu Ile Leu Glu Pro Arg Thr Tyr Arg 1765 1770 1775 Ile Leu Glu Gly Leu Tyr Pro Arg Ala Leu Ala Leu Glu Ala Ser Asn 1780 1785 1790 Val Ala Leu Gly Leu Tyr Ala Ser Asn Gly Leu Thr His Arg Ala Leu 1795 1800 1805 Ala Leu Tyr Ser Gly Leu Ala Ser Asn Pro His Glu Leu Tyr Ser Ala 1810 1815 1820 Ser Asn Ala Leu Ala Pro His Glu Gly Leu Ile Leu Glu Gly Leu Tyr 1825 1830 1835 1840 Gly Leu Tyr Ala Leu Ala Ala Leu Ala Ile Leu Glu Leu Glu Met Glu 1845 1850 1855 Thr Gly Leu Pro His Glu Ile Leu Glu Pro Arg Gly Leu Leu Glu Ile 1860 1865 1870 Leu Glu Val Ala Leu Pro Arg Ile Leu Glu Val Ala Leu Gly Leu Tyr 1875 1880 1885 Pro His Glu Pro His Glu Thr His Arg Leu Glu Gly Leu Ser Glu Arg 1890 1895 1900 Thr Tyr Arg Val Ala Leu Gly Leu Tyr Ala Ser Asn Leu Tyr Ser Gly 1905 1910 1915 1920 Leu Tyr His Ile Ser Ile Leu Glu Ile Leu Glu Met Glu Thr Thr His 1925 1930 1935 Arg Ile Leu Glu Ser Glu Arg Ala Ser Asn Ala Leu Ala Leu Glu Leu 1940 1945 1950 Tyr Ser Leu Tyr Ser Ala Arg Gly Ala Ser Pro Gly Leu Asn Leu Tyr 1955 1960 1965 Ser Thr Arg Pro Thr His Arg Ala Ser Pro Met Glu Thr Thr Tyr Arg 1970 1975 1980 Gly Leu Tyr Leu Glu Ile Leu Glu Val Ala Leu Ser Glu Arg Gly Leu 1985 1990 1995 2000 Asn Thr Arg Pro Leu Glu Ser Glu Arg Thr His Arg Val Ala Leu Ala 2005 2010 2015 Ser Asn Thr His Arg Gly Leu Asn Pro His Glu Thr Tyr Arg Thr His 2020 2025 2030 Arg Ile Leu Glu Leu Tyr Ser Gly Leu Ala Arg Gly Met Glu Thr Thr 2035 2040 2045 Tyr Arg Ala Ser Asn Ala Leu Ala Leu Glu Ala Ser Asn Ala Ser Asn 2050 2055 2060 Gly Leu Asn Ser Glu Arg Gly Leu Asn Ala Leu Ala Ile Leu Glu Gly 2065 2070 2075 2080 Leu Leu Tyr Ser Ile Leu Glu Ile Leu Glu Gly Leu Ala Ser Pro Gly 2085 2090 2095 Leu Asn Thr Tyr Arg Ala Ser Asn Ala Arg Gly Thr Tyr Arg Ser Glu 2100 2105 2110 Arg Gly Leu Gly Leu Ala Ser Pro Leu Tyr Ser Met Glu Thr Ala Ser 2115 2120 2125 Asn Ile Leu Glu Ala Ser Asn Ile Leu Glu Ala Ser Pro Pro His Glu 2130 2135 2140 Ala Ser Asn Ala Ser Pro Ile Leu Glu Ala Ser Pro Pro His Glu Leu 2145 2150 2155 2160 Tyr Ser Leu Glu Ala Ser Asn Gly Leu Asn Ser Glu Arg Ile Leu Glu 2165 2170 2175 Ala Ser Asn Leu Glu Ala Leu Ala Ile Leu Glu Ala Ser Asn Ala Ser 2180 2185 2190 Asn Ile Leu Glu Ala Ser Pro Ala Ser Pro Pro His Glu Ile Leu Glu 2195 2200 2205 Ala Ser Asn Gly Leu Asn Cys Tyr Ser Ser Glu Arg Ile Leu Glu Ser 2210 2215 2220 Glu Arg Thr Tyr Arg Leu Glu Met Glu Thr Ala Ser Asn Ala Arg Gly 2225 2230 2235 2240 Met Glu Thr Ile Leu Glu Pro Arg Leu Glu Ala Leu Ala Val Ala Leu 2245 2250 2255 Leu Tyr Ser Leu Tyr Ser Leu Glu Leu Tyr Ser Ala Ser Pro Pro His 2260 2265 2270 Glu Ala Ser Pro Ala Ser Pro Ala Ser Asn Leu Glu Leu Tyr Ser Ala 2275 2280 2285 Arg Gly Ala Ser Pro Leu Glu Leu Glu Gly Leu Thr Tyr Arg Ile Leu 2290 2295 2300 Glu Ala Ser Pro Thr His Arg Ala Ser Asn Gly Leu Leu Glu Thr Tyr 2305 2310 2315 2320 Arg Leu Glu Leu Glu Ala Ser Pro Gly Leu Val Ala Leu Ala Ser Asn 2325 2330 2335 Ile Leu Glu Leu Glu Leu Tyr Ser Ser Glu Arg Leu Tyr Ser Val Ala 2340 2345 2350 Leu Ala Ser Asn Ala Arg Gly His Ile Ser Leu Glu Leu Tyr Ser Ala 2355 2360 2365 Ser Pro Ser Glu Arg Ile Leu Glu Pro Arg Pro His Glu Ala Ser Pro 2370 2375 2380 Leu Glu Ser Glu Arg Leu Glu Thr Tyr Arg Thr His Arg Leu Tyr Ser 2385 2390 2395 2400 Ala Ser Pro Thr His Arg Ile Leu Glu Leu Glu Ile Leu Glu Gly Leu 2405 2410 2415 Asn Val Ala Leu Pro His Glu Ala Ser Asn Ala Ser Asn Thr Tyr Arg 2420 2425 2430 Ile Leu Glu Ser Glu Arg Ala Ser Asn Ile Leu Glu Ser Glu Arg Ser 2435 2440 2445 Glu Arg Ala Ser Asn Ala Leu Ala Ile Leu Glu Leu Glu Ser Glu Arg 2450 2455 2460 Leu Glu Ser Glu Arg Thr Tyr Arg Ala Arg Gly Gly Leu Tyr Gly Leu 2465 2470 2475 2480 Tyr Ala Arg Gly Leu Glu Ile Leu Glu Ala Ser Pro Ser Glu Arg Ser 2485 2490 2495 Glu Arg Gly Leu Tyr Thr Tyr Arg Gly Leu Tyr Ala Leu Ala Thr His 2500 2505 2510 Arg Met Glu Thr Ala Ser Asn Val Ala Leu Gly Leu Tyr Ser Glu Arg 2515 2520 2525 Ala Ser Pro Val Ala Leu Ile Leu Glu Pro His Glu Ala Ser Asn Ala 2530 2535 2540 Ser Pro Ile Leu Glu Gly Leu Tyr Ala Ser Asn Gly Leu Tyr Gly Leu 2545 2550 2555 2560 Asn Pro His Glu Leu Tyr Ser Leu Glu Ala Ser Asn Ala Ser Asn Ser 2565 2570 2575 Glu Arg Gly Leu Ala Ser Asn Ser Glu Arg Ala Ser Asn Ile Leu Glu 2580 2585 2590 Thr His Arg Ala Leu Ala His Ile Ser Gly Leu Asn Ser Glu Arg Leu 2595 2600 2605 Tyr Ser Pro His Glu Val Ala Leu Val Ala Leu Thr Tyr Arg Ala Ser 2610 2615 2620 Pro Ser Glu Arg Met Glu Thr Pro His Glu Ala Ser Pro Ala Ser Asn 2625 2630 2635 2640 Pro His Glu Ser Glu Arg Ile Leu Glu Ala Ser Asn Pro His Glu Thr 2645 2650 2655 Arg Pro Val Ala Leu Ala Arg Gly Thr His Arg Pro Arg Leu Tyr Ser 2660 2665 2670 Thr Tyr Arg Ala Ser Asn Ala Ser Asn Ala Ser Asn Ala Ser Pro Ile 2675 2680 2685 Leu Glu Gly Leu Asn Thr His Arg Thr Tyr Arg Leu Glu Gly Leu Asn 2690 2695 2700 Ala Ser Asn Gly Leu Thr Tyr Arg Thr His Arg Ile Leu Glu Ile Leu 2705 2710 2715 2720 Glu Ser Glu Arg Cys Tyr Ser Ile Leu Glu Leu Tyr Ser Ala Ser Asn 2725 2730 2735 Ala Ser Pro Ser Glu Arg Gly Leu Tyr Thr Arg Pro Leu Tyr Ser Val 2740 2745 2750 Ala Leu Ser Glu Arg Ile Leu Glu Leu Tyr Ser Gly Leu Tyr Ala Ser 2755 2760 2765 Asn Ala Arg Gly Ile Leu Glu Ile Leu Glu Thr Arg Pro Thr His Arg 2770 2775 2780 Leu Glu Ile Leu Glu Ala Ser Pro Val Ala Leu Ala Ser Asn Ala Leu 2785 2790 2795 2800 Ala Leu Tyr Ser Ser Glu Arg Leu Tyr Ser Ser Glu Arg Ile Leu Glu 2805 2810 2815 Pro His Glu Pro His Glu Gly Leu Thr Tyr Arg Ser Glu Arg Ile Leu 2820 2825 2830 Glu Leu Tyr Ser Ala Ser Pro Ala Ser Asn Ile Leu Glu Ser Glu Arg 2835 2840 2845 Ala Ser Pro Thr Tyr Arg Ile Leu Glu Ala Ser Asn Leu Tyr Ser Thr 2850 2855 2860 Arg Pro Pro His Glu Ser Glu Arg Ile Leu Glu Thr His Arg Ile Leu 2865 2870 2875 2880 Glu Thr His Arg Ala Ser Asn Ala Ser Pro Ala Arg Gly Leu Glu Gly 2885 2890 2895 Leu Tyr Ala Ser Asn Ala Leu Ala Ala Ser Asn Ile Leu Glu Thr Tyr 2900 2905 2910 Arg Ile Leu Glu Ala Ser Asn Gly Leu Tyr Ser Glu Arg Leu Glu Leu 2915 2920 2925 Tyr Ser Leu Tyr Ser Ser Glu Arg Gly Leu Leu Tyr Ser Ile Leu Glu 2930 2935 2940 Leu Glu Ala Ser Asn Leu Glu Ala Ser Pro Ala Arg Gly Ile Leu Glu 2945 2950 2955 2960 Ala Ser Asn Ser Glu Arg Ser Glu Arg Ala Ser Asn Ala Ser Pro Ile 2965 2970 2975 Leu Glu Ala Ser Pro Pro His Glu Leu Tyr Ser Leu Glu Ile Leu Glu 2980 2985 2990 Ala Ser Asn Cys Tyr Ser Thr His Arg Ala Ser Pro Thr His Arg Thr 2995 3000 3005 His Arg Leu Tyr Ser Pro His Glu Val Ala Leu Thr Arg Pro Ile Leu 3010 3015 3020 Glu Leu Tyr Ser Ala Ser Pro Pro His Glu Ala Ser Asn Ile Leu Glu 3025 3030 3035 3040 Pro His Glu Gly Leu Tyr Ala Arg Gly Gly Leu Leu Glu Ala Ser Asn 3045 3050 3055 Ala Leu Ala Thr His Arg Gly Leu Val Ala Leu Ser Glu Arg Ser Glu 3060 3065 3070 Arg Leu Glu Thr Tyr Arg Thr Arg Pro Ile Leu Glu Gly Leu Asn Ser 3075 3080 3085 Glu Arg Ser Glu Arg Thr His Arg Ala Ser Asn Thr His Arg Leu Glu 3090 3095 3100 Leu Tyr Ser Ala Ser Pro Pro His Glu Thr Arg Pro Gly Leu Tyr Ala 3105 3110 3115 3120 Ser Asn Pro Arg Leu Glu Ala Arg Gly Thr Tyr Arg Ala Ser Pro Thr 3125 3130 3135 His Arg Gly Leu Asn Thr Tyr Arg Thr Tyr Arg Leu Glu Pro His Glu 3140 3145 3150 Ala Ser Asn Gly Leu Asn Gly Leu Tyr Met Glu Thr Gly Leu Asn Ala 3155 3160 3165 Ser Asn Ile Leu Glu Thr Tyr Arg Ile Leu Glu Leu Tyr Ser Thr Tyr 3170 3175 3180 Arg Pro His Glu Ser Glu Arg Leu Tyr Ser Ala Leu Ala Ser Glu Arg 3185 3190 3195 3200 Met Glu Thr Gly Leu Tyr Gly Leu Thr His Arg Ala Leu Ala Pro Arg 3205 3210 3215 Ala Arg Gly Thr His Arg Ala Ser Asn Pro His Glu Ala Ser Asn Ala 3220 3225 3230 Ser Asn Ala Leu Ala Ala Leu Ala Ile Leu Glu Ala Ser Asn Thr Tyr 3235 3240 3245 Arg Gly Leu Asn Ala Ser Asn Leu Glu Thr Tyr Arg Leu Glu Gly Leu 3250 3255 3260 Tyr Leu Glu Ala Arg Gly Pro His Glu Ile Leu Glu Ile Leu Glu Leu 3265 3270 3275 3280 Tyr Ser Leu Tyr Ser Ala Leu Ala Ser Glu Arg Ala Ser Asn Ser Glu 3285 3290 3295 Arg Ala Arg Gly Ala Ser Asn Ile Leu Glu Ala Ser Asn Ala Ser Asn 3300 3305 3310 Ala Ser Pro Ala Ser Asn Ile Leu Glu Val Ala Leu Ala Arg Gly Gly 3315 3320 3325 Leu Gly Leu Tyr Ala Ser Pro Thr Tyr Arg Ile Leu Glu Thr Tyr Arg 3330 3335 3340 Leu Glu Ala Ser Asn Ile Leu Glu Ala Ser Pro Ala Ser Asn Ile Leu 3345 3350 3355 3360 Glu Ser Glu Arg Ala Ser Pro Gly Leu Ser Glu Arg Thr Tyr Arg Ala 3365 3370 3375 Arg Gly Val Ala Leu Thr Tyr Arg Val Ala Leu Leu Glu Val Ala Leu 3380 3385 3390 Ala Ser Asn Ser Glu Arg Leu Tyr Ser Gly Leu Ile Leu Glu Gly Leu 3395 3400 3405 Asn Thr His Arg Gly Leu Asn Leu Glu Pro His Glu Leu Glu Ala Leu 3410 3415 3420 Ala Pro Arg Ile Leu Glu Ala Ser Asn Ala Ser Pro Ala Ser Pro Pro 3425 3430 3435 3440 Arg Thr His Arg Pro His Glu Thr Tyr Arg Ala Ser Pro Val Ala Leu 3445 3450 3455 Leu Glu Gly Leu Asn Ile Leu Glu Leu Tyr Ser Leu Tyr Ser Thr Tyr 3460 3465 3470 Arg Thr Tyr Arg Gly Leu Leu Tyr Ser Thr His Arg Thr His Arg Thr 3475 3480 3485 Tyr Arg Ala Ser Asn Cys Tyr Ser Gly Leu Asn Ile Leu Glu Leu Glu 3490 3495 3500 Cys Tyr Ser Gly Leu Leu Tyr Ser Ala Ser Pro Thr His Arg Leu Tyr 3505 3510 3515 3520 Ser Thr His Arg Pro His Glu Gly Leu Tyr Leu Glu Pro His Glu Gly 3525 3530 3535 Leu Tyr Ile Leu Glu Gly Leu Tyr Leu Tyr Ser Pro His Glu Val Ala 3540 3545 3550 Leu Leu Tyr Ser Ala Ser Pro Thr Tyr Arg Gly Leu Tyr Thr Tyr Arg 3555 3560 3565 Val Ala Leu Thr Arg Pro Ala Ser Pro Thr His Arg Thr Tyr Arg Ala 3570 3575 3580 Ser Pro Ala Ser Asn Thr Tyr Arg Pro His Glu Cys Tyr Ser Ile Leu 3585 3590 3595 3600 Glu Ser Glu Arg Gly Leu Asn Thr Arg Pro Thr Tyr Arg Leu Glu Ala 3605 3610 3615 Arg Gly Ala Arg Gly Ile Leu Glu Ser Glu Arg Gly Leu Ala Ser Asn 3620 3625 3630 Ile Leu Glu Ala Ser Asn Leu Tyr Ser Leu Glu Ala Arg Gly Leu Glu 3635 3640 3645 Gly Leu Tyr Cys Tyr Ser Ala Ser Asn Thr Arg Pro Gly Leu Asn Pro 3650 3655 3660 His Glu Ile Leu Glu Pro Arg Val Ala Leu Ala Ser Pro Gly Leu Gly 3665 3670 3675 3680 Leu Tyr Thr Arg Pro Thr His Arg Gly Leu 3685 3690 <210> 15 <211> 4400 <212> DNA <213> Clostridium botulinum <400> 15 tagcattaaa aaaattagaa cctatagtaa ataaattaat taatatatag tttttataat 60 ttaattatga ataatattct taagataaaa agtaaatttt taaaaattta aattttcagt 120 ttacaaaaaa taacctgatt atgttatatg taattgtaaa aaacatataa aaaatcagaa 180 aaatttagga ggtatattat taatggatta aataataatt ttttaattta cttttgatta 240 ataaatatta aatgtttatt ttaattagga gatgatacgt atgccaataa ccataaataa 300 ttttagatat agtgatcctg ttaataatga tacaattatt atgatggagc caccatactg 360 taagggtcta gatatctatt ataaggcttt caaaataaca gatcgtattt ggatagtgcc 420 ggaaaggtat gaatttggga caaaacctga agattttaac ccaccatctt cattaataga 480 aggtgcatct gagtattacg atccaaatta tttaaggact gattctgata aagatagatt 540 tttacaaacc atggtaaaac tgtttaacag aattaaaaac aatgtagcag gtgaagcctt 600 attagataag ataataaatg ccatacctta ccttggaaat tcatattcct tactagacaa 660 gtttgataca aactctaatt cagtatcttt taatttatta gaacaagacc ccagtggagc 720 aactacaaaa tcagcaatgc tgacaaattt aataatattt ggacctgggc ctgttttaaa 780 taaaaatgag gttagaggta ttgtattgag ggtagataat aaaaattact tcccatgtag 840 agatggtttt ggctcaataa tgcaaatggc attttgccca gaatatgtac ctacctttga 900 taatgtaata gaaaatatta cgtcactcac tattggcaaa agcaaatatt ttcaagatcc 960 agcattacta ttaatgcacg aacttataca tgtactacat ggtttatacg gaatgcaggt 1020 atcaagccat gaaattattc catccaaaca agaaatttat atgcagcata catatccaat 1080 aagtgctgaa gaactattca cttttggcgg acaggatgct aatcttataa gtattgatat 1140 aaaaaacgat ttatatgaaa aaactttaaa tgattataaa gctatagcta acaaacttag 1200 tcaagtcact agctgcaatg atcccaacat tgatattgat agctacaaac aaatatatca 1260 acaaaaatat caattcgata aagatagcaa tggacaatat attgtaaatg aggataaatt 1320 tcagatacta tataatagca taatgtatgg ttttacagag attgaattgg gaaaaaaatt 1380 taatataaaa actagacttt cttattttag tatgaatcat gaccctgtaa aaattccaaa 1440 tttattagat gatacaattt acaatgatac agaaggattt aatatagaaa gcaaagatct 1500 gaaatctgaa tataaaggac aaaatatgag ggtaaataca aatgctttta gaaatgttga 1560 tggatcaggc ctagtttcaa aacttattgg cttatgtaaa aaaattatac caccaacaaa 1620 tataagagaa aatttatata atagaactgc atcattaaca gatttaggag gagaattatg 1680 tataaaaatt aaaaatgaag atttaacttt tatagctgaa aaaaatagct tttcagaaga 1740 accatttcaa gatgaaatag ttagttataa tacaaaaaat aaaccattaa attttaatta 1800 ttcgctagat aaaattattg tagattataa tctacaaagt aaaattacat tacctaatga 1860 taggacaacc ccagttacaa aaggaattcc atatgctcca gaatataaaa gtaatgctgc 1920 aagtacaata gaaatacata atattgatga caatacaata tatcaatatt tgtatgctca 1980 aaaatctcct acaactctac aaagaataac tatgactaat tctgttgatg acgcattaat 2040 aaattccacc aaaatatatt catattttcc atctgtaatc agtaaagtta accaaggtgc 2100 acaaggaatt ttattcttac agtgggtgag agatataatt gatgatttta ccaatgaatc 2160 ttcacaaaaa actactattg ataaaatttc agatgtatcc actattgttc cttatatagg 2220 acccgcatta aacattgtaa aacaaggcta tgagggaaac tttataggcg ctttagaaac 2280 taccggagtg gttttattat tagaatatat tccagaaatt actttaccag taattgcagc 2340 tttatctata gcagaaagta gcacacaaaa agaaaagata ataaaaacaa tagataactt 2400 tttagaaaaa agatatgaaa aatggattga agtatataaa ctagtaaaag caaaatggtt 2460 aggcacagtt aatacgcaat tccaaaaaag aagttatcaa atgtatagat ctttagaata 2520 tcaagtagat gcaataaaaa aaataataga ctatgaatat aaaatatatt caggacctga 2580 taaggaacaa attgccgacg aaattaataa tctgaaaaac aaacttgaag aaaaggctaa 2640 taaagcaatg ataaacataa atatatttat gagggaaagt tctagatcat ttttagttaa 2700 tcaaatgatt aacgaagcta aaaagcagtt attagagttt gatactcaaa gcaaaaatat 2760 tttaatgcag tatataaaag caaattctaa atttataggt ataactgaac taaaaaaatt 2820 agaatcaaaa ataaacaaag ttttttcaac accaattcca ttttcttatt ctaaaaatct 2880 ggattgttgg gttgataatg aagaagatat agatgttata ttaaaaaaga gtacaatttt 2940 aaatttagat attaataatg atattatatc agatatatct gggtttaatt catctgtaat 3000 aacatatcca gatgctcaat tggtgcccgg aataaatggc aaagcaatac atttagtaaa 3060 caatgaatct tctgaagtta tagtgcataa agctatggat attgaatata atgatatgtt 3120 taataatttt accgttagct tttggttgag ggttcctaaa gtatctgcta gtcatttaga 3180 acaatatggc acaaatgagt attcaataat tagctctatg aaaaaacata gtctatcaat 3240 aggatctggt tggagtgtat cacttaaagg taataactta atatggactt taaaagattc 3300 cgcgggagaa gttagacaaa taacttttag ggatttacct gataaattta atgcttattt 3360 agcaaataaa tgggttttta taactattac taatgataga ttatcttctg ctaatttgta 3420 tataaatgga gtacttatgg gaagtgcaga aattactggt ttaggagcta ttagagagga 3480 taataatata acattaaaac tagatagatg taataataat aatcaatacg tttctattga 3540 taaatttagg atattttgca aagcattaaa tccaaaagag attgaaaaat tatacacaag 3600 ttatttatct ataacctttt taagagactt ctggggaaac cctttacgat atgatacaga 3660 atattattta ataccagtag cttctagttc taaagatgtt caattgaaaa atataacaga 3720 ttatatgtat ttgacaaatg cgccatcgta tactaacgga aaattgaata tatattatag 3780 aaggttatat aatggactaa aatttattat aaaaagatat acacctaata atgaaataga 3840 ttcttttgtt aaatcaggtg attttattaa attatatgta tcatataaca ataatgagca 3900 cattgtaggt tatccgaaag atggaaatgc ctttaataat cttgatagaa ttctaagagt 3960 aggttataat gccccaggta tccctcttta taaaaaaatg gaagcagtaa aattgcgtga 4020 tttaaaaacc tattctgtac aacttaaatt atatgatgat aaaaatgcat ctttaggact 4080 agtaggtacc cataatggtc aaataggcaa cgatccaaat agggatatat taattgcaag 4140 caactggtac tttaatcatt taaaagataa aattttagga tgtgattggt actttgtacc 4200 tacagatgaa ggatggacaa atgattaaac agattgatat gttcatgatt actctatata 4260 aaaaattaaa taatataaca atctagctat attatttttg attattttct taatatatac 4320 taataaaata atcaaaatag agcctatctt aaattactga agggctgtgt caaaataaga 4380 ttttgacaca gcctctactt 4400 <210> 16 <211> 3708 <212> PRT <213> Clostridium tetani <400> 16 Met Glu Thr Pro Arg Ile Leu Glu Thr His Arg Ile Leu Glu Ala Ser 1 5 10 15 Asn Ala Ser Asn Pro His Glu Ala Arg Gly Thr Tyr Arg Ser Glu Arg 20 25 30 Ala Ser Pro Pro Arg Val Ala Leu Ala Ser Asn Ala Ser Asn Ala Ser 35 40 45 Pro Thr His Arg Ile Leu Glu Ile Leu Glu Met Glu Thr Met Glu Thr 50 55 60 Gly Leu Pro Arg Pro Arg Thr Tyr Arg Cys Tyr Ser Leu Tyr Ser Gly 65 70 75 80 Leu Tyr Leu Glu Ala Ser Pro Ile Leu Glu Thr Tyr Arg Thr Tyr Arg 85 90 95 Leu Tyr Ser Ala Leu Ala Pro His Glu Leu Tyr Ser Ile Leu Glu Thr 100 105 110 His Arg Ala Ser Pro Ala Arg Gly Ile Leu Glu Thr Arg Pro Ile Leu 115 120 125 Glu Val Ala Leu Pro Arg Gly Leu Ala Arg Gly Thr Tyr Arg Gly Leu 130 135 140 Pro His Glu Gly Leu Tyr Thr His Arg Leu Tyr Ser Pro Arg Gly Leu 145 150 155 160 Ala Ser Pro Pro His Glu Ala Ser Asn Pro Arg Pro Arg Ser Glu Arg 165 170 175 Ser Glu Arg Leu Glu Ile Leu Glu Gly Leu Gly Leu Tyr Ala Leu Ala 180 185 190 Ser Glu Arg Gly Leu Thr Tyr Arg Thr Tyr Arg Ala Ser Pro Pro Arg 195 200 205 Ala Ser Asn Thr Tyr Arg Leu Glu Ala Arg Gly Thr His Arg Ala Ser 210 215 220 Pro Ser Glu Arg Ala Ser Pro Leu Tyr Ser Ala Ser Pro Ala Arg Gly 225 230 235 240 Pro His Glu Leu Glu Gly Leu Asn Thr His Arg Met Glu Thr Val Ala 245 250 255 Leu Leu Tyr Ser Leu Glu Pro His Glu Ala Ser Asn Ala Arg Gly Ile 260 265 270 Leu Glu Leu Tyr Ser Ala Ser Asn Ala Ser Asn Val Ala Leu Ala Leu 275 280 285 Ala Gly Leu Tyr Gly Leu Ala Leu Ala Leu Glu Leu Glu Ala Ser Pro 290 295 300 Leu Tyr Ser Ile Leu Glu Ile Leu Glu Ala Ser Asn Ala Leu Ala Ile 305 310 315 320 Leu Glu Pro Arg Thr Tyr Arg Leu Glu Gly Leu Tyr Ala Ser Asn Ser 325 330 335 Glu Arg Thr Tyr Arg Ser Glu Arg Leu Glu Leu Glu Ala Ser Pro Leu 340 345 350 Tyr Ser Pro His Glu Ala Ser Pro Thr His Arg Ala Ser Asn Ser Glu 355 360 365 Arg Ala Ser Asn Ser Glu Arg Val Ala Leu Ser Glu Arg Pro His Glu 370 375 380 Ala Ser Asn Leu Glu Leu Glu Gly Leu Gly Leu Asn Ala Ser Pro Pro 385 390 395 400 Arg Ser Glu Arg Gly Leu Tyr Ala Leu Ala Thr His Arg Thr His Arg 405 410 415 Leu Tyr Ser Ser Glu Arg Ala Leu Ala Met Glu Thr Leu Glu Thr His 420 425 430 Arg Ala Ser Asn Leu Glu Ile Leu Glu Ile Leu Glu Pro His Glu Gly 435 440 445 Leu Tyr Pro Arg Gly Leu Tyr Pro Arg Val Ala Leu Leu Glu Ala Ser 450 455 460 Asn Leu Tyr Ser Ala Ser Asn Gly Leu Val Ala Leu Ala Arg Gly Gly 465 470 475 480 Leu Tyr Ile Leu Glu Val Ala Leu Leu Glu Ala Arg Gly Val Ala Leu 485 490 495 Ala Ser Pro Ala Ser Asn Leu Tyr Ser Ala Ser Asn Thr Tyr Arg Pro 500 505 510 His Glu Pro Arg Cys Tyr Ser Ala Arg Gly Ala Ser Pro Gly Leu Tyr 515 520 525 Pro His Glu Gly Leu Tyr Ser Glu Arg Ile Leu Glu Met Glu Thr Gly 530 535 540 Leu Asn Met Glu Thr Ala Leu Ala Pro His Glu Cys Tyr Ser Pro Arg 545 550 555 560 Gly Leu Thr Tyr Arg Val Ala Leu Pro Arg Thr His Arg Pro His Glu 565 570 575 Ala Ser Pro Ala Ser Asn Val Ala Leu Ile Leu Glu Gly Leu Ala Ser 580 585 590 Asn Ile Leu Glu Thr His Arg Ser Glu Arg Leu Glu Thr His Arg Ile 595 600 605 Leu Glu Gly Leu Tyr Leu Tyr Ser Ser Glu Arg Leu Tyr Ser Thr Tyr 610 615 620 Arg Pro His Glu Gly Leu Asn Ala Ser Pro Pro Arg Ala Leu Ala Leu 625 630 635 640 Glu Leu Glu Leu Glu Met Glu Thr His Ile Ser Gly Leu Leu Glu Ile 645 650 655 Leu Glu His Ile Ser Val Ala Leu Leu Glu His Ile Ser Gly Leu Tyr 660 665 670 Leu Glu Thr Tyr Arg Gly Leu Tyr Met Glu Thr Gly Leu Asn Val Ala 675 680 685 Leu Ser Glu Arg Ser Glu Arg His Ile Ser Gly Leu Ile Leu Glu Ile 690 695 700 Leu Glu Pro Arg Ser Glu Arg Leu Tyr Ser Gly Leu Asn Gly Leu Ile 705 710 715 720 Leu Glu Thr Tyr Arg Met Glu Thr Gly Leu Asn His Ile Ser Thr His 725 730 735 Arg Thr Tyr Arg Pro Arg Ile Leu Glu Ser Glu Arg Ala Leu Ala Gly 740 745 750 Leu Gly Leu Leu Glu Pro His Glu Thr His Arg Pro His Glu Gly Leu 755 760 765 Tyr Gly Leu Tyr Gly Leu Asn Ala Ser Pro Ala Leu Ala Ala Ser Asn 770 775 780 Leu Glu Ile Leu Glu Ser Glu Arg Ile Leu Glu Ala Ser Pro Ile Leu 785 790 795 800 Glu Leu Tyr Ser Ala Ser Asn Ala Ser Pro Leu Glu Thr Tyr Arg Gly 805 810 815 Leu Leu Tyr Ser Thr His Arg Leu Glu Ala Ser Asn Ala Ser Pro Thr 820 825 830 Tyr Arg Leu Tyr Ser Ala Leu Ala Ile Leu Glu Ala Leu Ala Ala Ser 835 840 845 Asn Leu Tyr Ser Leu Glu Ser Glu Arg Gly Leu Asn Val Ala Leu Thr 850 855 860 His Arg Ser Glu Arg Cys Tyr Ser Ala Ser Asn Ala Ser Pro Pro Arg 865 870 875 880 Ala Ser Asn Ile Leu Glu Ala Ser Pro Ile Leu Glu Ala Ser Pro Ser 885 890 895 Glu Arg Thr Tyr Arg Leu Tyr Ser Gly Leu Asn Ile Leu Glu Thr Tyr 900 905 910 Arg Gly Leu Asn Gly Leu Asn Leu Tyr Ser Thr Tyr Arg Gly Leu Asn 915 920 925 Pro His Glu Ala Ser Pro Leu Tyr Ser Ala Ser Pro Ser Glu Arg Ala 930 935 940 Ser Asn Gly Leu Tyr Gly Leu Asn Thr Tyr Arg Ile Leu Glu Val Ala 945 950 955 960 Leu Ala Ser Asn Gly Leu Ala Ser Pro Leu Tyr Ser Pro His Glu Gly 965 970 975 Leu Asn Ile Leu Glu Leu Glu Thr Tyr Arg Ala Ser Asn Ser Glu Arg 980 985 990 Ile Leu Glu Met Glu Thr Thr Tyr Arg Gly Leu Tyr Pro His Glu Thr 995 1000 1005 His Arg Gly Leu Ile Leu Glu Gly Leu Leu Glu Gly Leu Tyr Leu Tyr 1010 1015 1020 Ser Leu Tyr Ser Pro His Glu Ala Ser Asn Ile Leu Glu Leu Tyr Ser 1025 1030 1035 1040 Thr His Arg Ala Arg Gly Leu Glu Ser Glu Arg Thr Tyr Arg Pro His 1045 1050 1055 Glu Ser Glu Arg Met Glu Thr Ala Ser Asn His Ile Ser Ala Ser Pro 1060 1065 1070 Pro Arg Val Ala Leu Leu Tyr Ser Ile Leu Glu Pro Arg Ala Ser Asn 1075 1080 1085 Leu Glu Leu Glu Ala Ser Pro Ala Ser Pro Thr His Arg Ile Leu Glu 1090 1095 1100 Thr Tyr Arg Ala Ser Asn Ala Ser Pro Thr His Arg Gly Leu Gly Leu 1105 1110 1115 1120 Tyr Pro His Glu Ala Ser Asn Ile Leu Glu Gly Leu Ser Glu Arg Leu 1125 1130 1135 Tyr Ser Ala Ser Pro Leu Glu Leu Tyr Ser Ser Glu Arg Gly Leu Thr 1140 1145 1150 Tyr Arg Leu Tyr Ser Gly Leu Tyr Gly Leu Asn Ala Ser Asn Met Glu 1155 1160 1165 Thr Ala Arg Gly Val Ala Leu Ala Ser Asn Thr His Arg Ala Ser Asn 1170 1175 1180 Ala Leu Ala Pro His Glu Ala Arg Gly Ala Ser Asn Val Ala Leu Ala 1185 1190 1195 1200 Ser Pro Gly Leu Tyr Ser Glu Arg Gly Leu Tyr Leu Glu Val Ala Leu 1205 1210 1215 Ser Glu Arg Leu Tyr Ser Leu Glu Ile Leu Glu Gly Leu Tyr Leu Glu 1220 1225 1230 Cys Tyr Ser Leu Tyr Ser Leu Tyr Ser Ile Leu Glu Ile Leu Glu Pro 1235 1240 1245 Arg Pro Arg Thr His Arg Ala Ser Asn Ile Leu Glu Ala Arg Gly Gly 1250 1255 1260 Leu Ala Ser Asn Leu Glu Thr Tyr Arg Ala Ser Asn Ala Arg Gly Thr 1265 1270 1275 1280 His Arg Ala Leu Ala Ser Glu Arg Leu Glu Thr His Arg Ala Ser Pro 1285 1290 1295 Leu Glu Gly Leu Tyr Gly Leu Tyr Gly Leu Leu Glu Cys Tyr Ser Ile 1300 1305 1310 Leu Glu Leu Tyr Ser Ile Leu Glu Leu Tyr Ser Ala Ser Asn Gly Leu 1315 1320 1325 Ala Ser Pro Leu Glu Thr His Arg Pro His Glu Ile Leu Glu Ala Leu 1330 1335 1340 Ala Gly Leu Leu Tyr Ser Ala Ser Asn Ser Glu Arg Pro His Glu Ser 1345 1350 1355 1360 Glu Arg Gly Leu Gly Leu Pro Arg Pro His Glu Gly Leu Asn Ala Ser 1365 1370 1375 Pro Gly Leu Ile Leu Glu Val Ala Leu Ser Glu Arg Thr Tyr Arg Ala 1380 1385 1390 Ser Asn Thr His Arg Leu Tyr Ser Ala Ser Asn Leu Tyr Ser Pro Arg 1395 1400 1405 Leu Glu Ala Ser Asn Pro His Glu Ala Ser Asn Thr Tyr Arg Ser Glu 1410 1415 1420 Arg Leu Glu Ala Ser Pro Leu Tyr Ser Ile Leu Glu Ile Leu Glu Val 1425 1430 1435 1440 Ala Leu Ala Ser Pro Thr Tyr Arg Ala Ser Asn Leu Glu Gly Leu Asn 1445 1450 1455 Ser Glu Arg Leu Tyr Ser Ile Leu Glu Thr His Arg Leu Glu Pro Arg 1460 1465 1470 Ala Ser Asn Ala Ser Pro Ala Arg Gly Thr His Arg Thr His Arg Pro 1475 1480 1485 Arg Val Ala Leu Thr His Arg Leu Tyr Ser Gly Leu Tyr Ile Leu Glu 1490 1495 1500 Pro Arg Thr Tyr Arg Ala Leu Ala Pro Arg Gly Leu Thr Tyr Arg Leu 1505 1510 1515 1520 Tyr Ser Ser Glu Arg Ala Ser Asn Ala Leu Ala Ala Leu Ala Ser Glu 1525 1530 1535 Arg Thr His Arg Ile Leu Glu Gly Leu Ile Leu Glu His Ile Ser Ala 1540 1545 1550 Ser Asn Ile Leu Glu Ala Ser Pro Ala Ser Pro Ala Ser Asn Thr His 1555 1560 1565 Arg Ile Leu Glu Thr Tyr Arg Gly Leu Asn Thr Tyr Arg Leu Glu Thr 1570 1575 1580 Tyr Arg Ala Leu Ala Gly Leu Asn Leu Tyr Ser Ser Glu Arg Pro Arg 1585 1590 1595 1600 Thr His Arg Thr His Arg Leu Glu Gly Leu Asn Ala Arg Gly Ile Leu 1605 1610 1615 Glu Thr His Arg Met Glu Thr Thr His Arg Ala Ser Asn Ser Glu Arg 1620 1625 1630 Val Ala Leu Ala Ser Pro Ala Ser Pro Ala Leu Ala Leu Glu Ile Leu 1635 1640 1645 Glu Ala Ser Asn Ser Glu Arg Thr His Arg Leu Tyr Ser Ile Leu Glu 1650 1655 1660 Thr Tyr Arg Ser Glu Arg Thr Tyr Arg Pro His Glu Pro Arg Ser Glu 1665 1670 1675 1680 Arg Val Ala Leu Ile Leu Glu Ser Glu Arg Leu Tyr Ser Val Ala Leu 1685 1690 1695 Ala Ser Asn Gly Leu Asn Gly Leu Tyr Ala Leu Ala Gly Leu Asn Gly 1700 1705 1710 Leu Tyr Ile Leu Glu Leu Glu Pro His Glu Leu Glu Gly Leu Asn Thr 1715 1720 1725 Arg Pro Val Ala Leu Ala Arg Gly Ala Ser Pro Ile Leu Glu Ile Leu 1730 1735 1740 Glu Ala Ser Pro Ala Ser Pro Pro His Glu Thr His Arg Ala Ser Asn 1745 1750 1755 1760 Gly Leu Ser Glu Arg Ser Glu Arg Gly Leu Asn Leu Tyr Ser Thr His 1765 1770 1775 Arg Thr His Arg Ile Leu Glu Ala Ser Pro Leu Tyr Ser Ile Leu Glu 1780 1785 1790 Ser Glu Arg Ala Ser Pro Val Ala Leu Ser Glu Arg Thr His Arg Ile 1795 1800 1805 Leu Glu Val Ala Leu Pro Arg Thr Tyr Arg Ile Leu Glu Gly Leu Tyr 1810 1815 1820 Pro Arg Ala Leu Ala Leu Glu Ala Ser Asn Ile Leu Glu Val Ala Leu 1825 1830 1835 1840 Leu Tyr Ser Gly Leu Asn Gly Leu Tyr Thr Tyr Arg Gly Leu Gly Leu 1845 1850 1855 Tyr Ala Ser Asn Pro His Glu Ile Leu Glu Gly Leu Tyr Ala Leu Ala 1860 1865 1870 Leu Glu Gly Leu Thr His Arg Thr His Arg Gly Leu Tyr Val Ala Leu 1875 1880 1885 Val Ala Leu Leu Glu Leu Glu Leu Glu Gly Leu Thr Tyr Arg Ile Leu 1890 1895 1900 Glu Pro Arg Gly Leu Ile Leu Glu Thr His Arg Leu Glu Pro Arg Val 1905 1910 1915 1920 Ala Leu Ile Leu Glu Ala Leu Ala Ala Leu Ala Leu Glu Ser Glu Arg 1925 1930 1935 Ile Leu Glu Ala Leu Ala Gly Leu Ser Glu Arg Ser Glu Arg Thr His 1940 1945 1950 Arg Gly Leu Asn Leu Tyr Ser Gly Leu Leu Tyr Ser Ile Leu Glu Ile 1955 1960 1965 Leu Glu Leu Tyr Ser Thr His Arg Ile Leu Glu Ala Ser Pro Ala Ser 1970 1975 1980 Asn Pro His Glu Leu Glu Gly Leu Leu Tyr Ser Ala Arg Gly Thr Tyr 1985 1990 1995 2000 Arg Gly Leu Leu Tyr Ser Thr Arg Pro Ile Leu Glu Gly Leu Val Ala 2005 2010 2015 Leu Thr Tyr Arg Leu Tyr Ser Leu Glu Val Ala Leu Leu Tyr Ser Ala 2020 2025 2030 Leu Ala Leu Tyr Ser Thr Arg Pro Leu Glu Gly Leu Tyr Thr His Arg 2035 2040 2045 Val Ala Leu Ala Ser Asn Thr His Arg Gly Leu Asn Pro His Glu Gly 2050 2055 2060 Leu Asn Leu Tyr Ser Ala Arg Gly Ser Glu Arg Thr Tyr Arg Gly Leu 2065 2070 2075 2080 Asn Met Glu Thr Thr Tyr Arg Ala Arg Gly Ser Glu Arg Leu Glu Gly 2085 2090 2095 Leu Thr Tyr Arg Gly Leu Asn Val Ala Leu Ala Ser Pro Ala Leu Ala 2100 2105 2110 Ile Leu Glu Leu Tyr Ser Leu Tyr Ser Ile Leu Glu Ile Leu Glu Ala 2115 2120 2125 Ser Pro Thr Tyr Arg Gly Leu Thr Tyr Arg Leu Tyr Ser Ile Leu Glu 2130 2135 2140 Thr Tyr Arg Ser Glu Arg Gly Leu Tyr Pro Arg Ala Ser Pro Leu Tyr 2145 2150 2155 2160 Ser Gly Leu Gly Leu Asn Ile Leu Glu Ala Leu Ala Ala Ser Pro Gly 2165 2170 2175 Leu Ile Leu Glu Ala Ser Asn Ala Ser Asn Leu Glu Leu Tyr Ser Ala 2180 2185 2190 Ser Asn Leu Tyr Ser Leu Glu Gly Leu Gly Leu Leu Tyr Ser Ala Leu 2195 2200 2205 Ala Ala Ser Asn Leu Tyr Ser Ala Leu Ala Met Glu Thr Ile Leu Glu 2210 2215 2220 Ala Ser Asn Ile Leu Glu Ala Ser Asn Ile Leu Glu Pro His Glu Met 2225 2230 2235 2240 Glu Thr Ala Arg Gly Gly Leu Ser Glu Arg Ser Glu Arg Ala Arg Gly 2245 2250 2255 Ser Glu Arg Pro His Glu Leu Glu Val Ala Leu Ala Ser Asn Gly Leu 2260 2265 2270 Asn Met Glu Thr Ile Leu Glu Ala Ser Asn Gly Leu Ala Leu Ala Leu 2275 2280 2285 Tyr Ser Leu Tyr Ser Gly Leu Asn Leu Glu Leu Glu Gly Leu Pro His 2290 2295 2300 Glu Ala Ser Pro Thr His Arg Gly Leu Asn Ser Glu Arg Leu Tyr Ser 2305 2310 2315 2320 Ala Ser Asn Ile Leu Glu Leu Glu Met Glu Thr Gly Leu Asn Thr Tyr 2325 2330 2335 Arg Ile Leu Glu Leu Tyr Ser Ala Leu Ala Ala Ser Asn Ser Glu Arg 2340 2345 2350 Leu Tyr Ser Pro His Glu Ile Leu Glu Gly Leu Tyr Ile Leu Glu Thr 2355 2360 2365 His Arg Gly Leu Leu Glu Leu Tyr Ser Leu Tyr Ser Leu Glu Gly Leu 2370 2375 2380 Ser Glu Arg Leu Tyr Ser Ile Leu Glu Ala Ser Asn Leu Tyr Ser Val 2385 2390 2395 2400 Ala Leu Pro His Glu Ser Glu Arg Thr His Arg Pro Arg Ile Leu Glu 2405 2410 2415 Pro Arg Pro His Glu Ser Glu Arg Thr Tyr Arg Ser Glu Arg Leu Tyr 2420 2425 2430 Ser Ala Ser Asn Leu Glu Ala Ser Pro Cys Tyr Ser Thr Arg Pro Val 2435 2440 2445 Ala Leu Ala Ser Pro Ala Ser Asn Gly Leu Gly Leu Ala Ser Pro Ile 2450 2455 2460 Leu Glu Ala Ser Pro Val Ala Leu Ile Leu Glu Leu Glu Leu Tyr Ser 2465 2470 2475 2480 Leu Tyr Ser Ser Glu Arg Thr His Arg Ile Leu Glu Leu Glu Ala Ser 2485 2490 2495 Asn Leu Glu Ala Ser Pro Ile Leu Glu Ala Ser Asn Ala Ser Asn Ala 2500 2505 2510 Ser Pro Ile Leu Glu Ile Leu Glu Ser Glu Arg Ala Ser Pro Ile Leu 2515 2520 2525 Glu Ser Glu Arg Gly Leu Tyr Pro His Glu Ala Ser Asn Ser Glu Arg 2530 2535 2540 Ser Glu Arg Val Ala Leu Ile Leu Glu Thr His Arg Thr Tyr Arg Pro 2545 2550 2555 2560 Arg Ala Ser Pro Ala Leu Ala Gly Leu Asn Leu Glu Val Ala Leu Pro 2565 2570 2575 Arg Gly Leu Tyr Ile Leu Glu Ala Ser Asn Gly Leu Tyr Leu Tyr Ser 2580 2585 2590 Ala Leu Ala Ile Leu Glu His Ile Ser Leu Glu Val Ala Leu Ala Ser 2595 2600 2605 Asn Ala Ser Asn Gly Leu Ser Glu Arg Ser Glu Arg Gly Leu Val Ala 2610 2615 2620 Leu Ile Leu Glu Val Ala Leu His Ile Ser Leu Tyr Ser Ala Leu Ala 2625 2630 2635 2640 Met Glu Thr Ala Ser Pro Ile Leu Glu Gly Leu Thr Tyr Arg Ala Ser 2645 2650 2655 Asn Ala Ser Pro Met Glu Thr Pro His Glu Ala Ser Asn Ala Ser Asn 2660 2665 2670 Pro His Glu Thr His Arg Val Ala Leu Ser Glu Arg Pro His Glu Thr 2675 2680 2685 Arg Pro Leu Glu Ala Arg Gly Val Ala Leu Pro Arg Leu Tyr Ser Val 2690 2695 2700 Ala Leu Ser Glu Arg Ala Leu Ala Ser Glu Arg His Ile Ser Leu Glu 2705 2710 2715 2720 Gly Leu Gly Leu Asn Thr Tyr Arg Gly Leu Tyr Thr His Arg Ala Ser 2725 2730 2735 Asn Gly Leu Thr Tyr Arg Ser Glu Arg Ile Leu Glu Ile Leu Glu Ser 2740 2745 2750 Glu Arg Ser Glu Arg Met Glu Thr Leu Tyr Ser Leu Tyr Ser His Ile 2755 2760 2765 Ser Ser Glu Arg Leu Glu Ser Glu Arg Ile Leu Glu Gly Leu Tyr Ser 2770 2775 2780 Glu Arg Gly Leu Tyr Thr Arg Pro Ser Glu Arg Val Ala Leu Ser Glu 2785 2790 2795 2800 Arg Leu Glu Leu Tyr Ser Gly Leu Tyr Ala Ser Asn Ala Ser Asn Leu 2805 2810 2815 Glu Ile Leu Glu Thr Arg Pro Thr His Arg Leu Glu Leu Tyr Ser Ala 2820 2825 2830 Ser Pro Ser Glu Arg Ala Leu Ala Gly Leu Tyr Gly Leu Val Ala Leu 2835 2840 2845 Ala Arg Gly Gly Leu Asn Ile Leu Glu Thr His Arg Pro His Glu Ala 2850 2855 2860 Arg Gly Ala Ser Pro Leu Glu Pro Arg Ala Ser Pro Leu Tyr Ser Pro 2865 2870 2875 2880 His Glu Ala Ser Asn Ala Leu Ala Thr Tyr Arg Leu Glu Ala Leu Ala 2885 2890 2895 Ala Ser Asn Leu Tyr Ser Thr Arg Pro Val Ala Leu Pro His Glu Ile 2900 2905 2910 Leu Glu Thr His Arg Ile Leu Glu Thr His Arg Ala Ser Asn Ala Ser 2915 2920 2925 Pro Ala Arg Gly Leu Glu Ser Glu Arg Ser Glu Arg Ala Leu Ala Ala 2930 2935 2940 Ser Asn Leu Glu Thr Tyr Arg Ile Leu Glu Ala Ser Asn Gly Leu Tyr 2945 2950 2955 2960 Val Ala Leu Leu Glu Met Glu Thr Gly Leu Tyr Ser Glu Arg Ala Leu 2965 2970 2975 Ala Gly Leu Ile Leu Glu Thr His Arg Gly Leu Tyr Leu Glu Gly Leu 2980 2985 2990 Tyr Ala Leu Ala Ile Leu Glu Ala Arg Gly Gly Leu Ala Ser Pro Ala 2995 3000 3005 Ser Asn Ala Ser Asn Ile Leu Glu Thr His Arg Leu Glu Leu Tyr Ser 3010 3015 3020 Leu Glu Ala Ser Pro Ala Arg Gly Cys Tyr Ser Ala Ser Asn Ala Ser 3025 3030 3035 3040 Asn Ala Ser Asn Ala Ser Asn Gly Leu Asn Thr Tyr Arg Val Ala Leu 3045 3050 3055 Ser Glu Arg Ile Leu Glu Ala Ser Pro Leu Tyr Ser Pro His Glu Ala 3060 3065 3070 Arg Gly Ile Leu Glu Pro His Glu Cys Tyr Ser Leu Tyr Ser Ala Leu 3075 3080 3085 Ala Leu Glu Ala Ser Asn Pro Arg Leu Tyr Ser Gly Leu Ile Leu Glu 3090 3095 3100 Gly Leu Leu Tyr Ser Leu Glu Thr Tyr Arg Thr His Arg Ser Glu Arg 3105 3110 3115 3120 Thr Tyr Arg Leu Glu Ser Glu Arg Ile Leu Glu Thr His Arg Pro His 3125 3130 3135 Glu Leu Glu Ala Arg Gly Ala Ser Pro Pro His Glu Thr Arg Pro Gly 3140 3145 3150 Leu Tyr Ala Ser Asn Pro Arg Leu Glu Ala Arg Gly Thr Tyr Arg Ala 3155 3160 3165 Ser Pro Thr His Arg Gly Leu Thr Tyr Arg Thr Tyr Arg Leu Glu Ile 3170 3175 3180 Leu Glu Pro Arg Val Ala Leu Ala Leu Ala Ser Glu Arg Ser Glu Arg 3185 3190 3195 3200 Ser Glu Arg Leu Tyr Ser Ala Ser Pro Val Ala Leu Gly Leu Asn Leu 3205 3210 3215 Glu Leu Tyr Ser Ala Ser Asn Ile Leu Glu Thr His Arg Ala Ser Pro 3220 3225 3230 Thr Tyr Arg Met Glu Thr Thr Tyr Arg Leu Glu Thr His Arg Ala Ser 3235 3240 3245 Asn Ala Leu Ala Pro Arg Ser Glu Arg Thr Tyr Arg Thr His Arg Ala 3250 3255 3260 Ser Asn Gly Leu Tyr Leu Tyr Ser Leu Glu Ala Ser Asn Ile Leu Glu 3265 3270 3275 3280 Thr Tyr Arg Thr Tyr Arg Ala Arg Gly Ala Arg Gly Leu Glu Thr Tyr 3285 3290 3295 Arg Ala Ser Asn Gly Leu Tyr Leu Glu Leu Tyr Ser Pro His Glu Ile 3300 3305 3310 Leu Glu Ile Leu Glu Leu Tyr Ser Ala Arg Gly Thr Tyr Arg Thr His 3315 3320 3325 Arg Pro Arg Ala Ser Asn Ala Ser Asn Gly Leu Ile Leu Glu Ala Ser 3330 3335 3340 Pro Ser Glu Arg Pro His Glu Val Ala Leu Leu Tyr Ser Ser Glu Arg 3345 3350 3355 3360 Gly Leu Tyr Ala Ser Pro Pro His Glu Ile Leu Glu Leu Tyr Ser Leu 3365 3370 3375 Glu Thr Tyr Arg Val Ala Leu Ser Glu Arg Thr Tyr Arg Ala Ser Asn 3380 3385 3390 Ala Ser Asn Ala Ser Asn Gly Leu His Ile Ser Ile Leu Glu Val Ala 3395 3400 3405 Leu Gly Leu Tyr Thr Tyr Arg Pro Arg Leu Tyr Ser Ala Ser Pro Gly 3410 3415 3420 Leu Tyr Ala Ser Asn Ala Leu Ala Pro His Glu Ala Ser Asn Ala Ser 3425 3430 3435 3440 Asn Leu Glu Ala Ser Pro Ala Arg Gly Ile Leu Glu Leu Glu Ala Arg 3445 3450 3455 Gly Val Ala Leu Gly Leu Tyr Thr Tyr Arg Ala Ser Asn Ala Leu Ala 3460 3465 3470 Pro Arg Gly Leu Tyr Ile Leu Glu Pro Arg Leu Glu Thr Tyr Arg Leu 3475 3480 3485 Tyr Ser Leu Tyr Ser Met Glu Thr Gly Leu Ala Leu Ala Val Ala Leu 3490 3495 3500 Leu Tyr Ser Leu Glu Ala Arg Gly Ala Ser Pro Leu Glu Leu Tyr Ser 3505 3510 3515 3520 Thr His Arg Thr Tyr Arg Ser Glu Arg Val Ala Leu Gly Leu Asn Leu 3525 3530 3535 Glu Leu Tyr Ser Leu Glu Thr Tyr Arg Ala Ser Pro Ala Ser Pro Leu 3540 3545 3550 Tyr Ser Ala Ser Asn Ala Leu Ala Ser Glu Arg Leu Glu Gly Leu Tyr 3555 3560 3565 Leu Glu Val Ala Leu Gly Leu Tyr Thr His Arg His Ile Ser Ala Ser 3570 3575 3580 Asn Gly Leu Tyr Gly Leu Asn Ile Leu Glu Gly Leu Tyr Ala Ser Asn 3585 3590 3595 3600 Ala Ser Pro Pro Arg Ala Ser Asn Ala Arg Gly Ala Ser Pro Ile Leu 3605 3610 3615 Glu Leu Glu Ile Leu Glu Ala Leu Ala Ser Glu Arg Ala Ser Asn Thr 3620 3625 3630 Arg Pro Thr Tyr Arg Pro His Glu Ala Ser Asn His Ile Ser Leu Glu 3635 3640 3645 Leu Tyr Ser Ala Ser Pro Leu Tyr Ser Ile Leu Glu Leu Glu Gly Leu 3650 3655 3660 Tyr Cys Tyr Ser Ala Ser Pro Thr Arg Pro Thr Tyr Arg Pro His Glu 3665 3670 3675 3680 Val Ala Leu Pro Arg Thr His Arg Ala Ser Pro Gly Leu Gly Leu Tyr 3685 3690 3695 Thr Arg Pro Thr His Arg Ala Ser Asn Ala Ser Pro 3700 3705 <210> 17 <211> 31 <212> PRT <213> Artificial Sequence <220> <223> cleavage site <400> 17 Lys Leu Leu Cys Val Arg Gly Ile Ile Thr Ser Lys Thr Lys Ser Leu 1 5 10 15 Asp Lys Gly Tyr Asn Lys Ala Leu Asn Asp Leu Cys Ile Lys Val 20 25 30 <210> 18 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> cleavage site <400> 18 Ile Gln Met Cys Lys Ser Val Lys Ala Pro Gly Ile Cys Ile Asp Val 1 5 10 15 <210> 19 <211> 25 <212> PRT <213> Artificial Sequence <220> <223> cleavage site <400> 19 Thr Lys Phe Cys His Lys Ala Ile Asp Gly Arg Ser Leu Tyr Asn Lys 1 5 10 15 Thr Leu Asp Cys Arg Glu Leu Leu Val 20 25 <210> 20 <211> 20 <212> PRT <213> Artificial Sequence <220> <223> cleavage site <400> 20 Thr Lys Val Cys Leu Arg Leu Thr Lys Asn Ser Arg Asp Asp Ser Thr 1 5 10 15 Cys Ile Lys Val 20 <210> 21 <211> 21 <212> PRT <213> Artificial Sequence <220> <223> cleavage site <400> 21 Ile Arg Phe Cys Lys Asn Ile Val Ser Val Lys Gly Ile Arg Lys Ser 1 5 10 15 Ile Cys Ile Glu Ile 20 <210> 22 <211> 23 <212> PRT <213> Artificial Sequence <220> <223> cleavage site <400> 22 Val Lys Phe Cys Lys Ser Val Ile Pro Arg Lys Gly Thr Lys Ala Pro 1 5 10 15 Pro Arg Leu Cys Ile Arg Val 20 <210> 23 <211> 21 <212> PRT <213> Artificial Sequence <220> <223> cleavage site <400> 23 Ile Ala Met Cys Lys Pro Val Met Tyr Lys Asn Thr Gly Lys Ser Glu 1 5 10 15 Gln Cys Ile Ile Val 20 <210> 24 <211> 35 <212> PRT <213> Artificial Sequence <220> <223> cleavage site <400> 24 Ile Gly Leu Cys Lys Lys Ile Ile Pro Pro Thr Asn Ile Arg Glu Asn 1 5 10 15 Leu Tyr Asn Arg Thr Ala Ser Leu Thr Asp Leu Gly Gly Glu Leu Cys 20 25 30 Ile Lys Ile 35 <210> 25 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> ligase recognition motif <400> 25 Ala Leu Ala Pro Tyr Ile Pro 1 5 <210> 26 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> ligase recognition motif <400> 26 Arg Phe Met Asp Tyr Trp Glu Gly Leu 1 5 <210> 27 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> ligase recognition motif <220> <221> MISC_FEATURE <222> (2)..(4) <223> Xaa can be any naturally occurring amino acid <220> <221> MISC_FEATURE <222> (7)..(8) <223> Xaa can be any naturally occurring amino acid <400> 27 Phe Xaa Xaa Xaa Leu Trp Xaa Xaa Leu 1 5 <210> 28 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> ligase recognition motif <400> 28 Glu Leu Glu Ser Pro Pro Pro Pro Tyr Ser Arg Tyr Pro Met 1 5 10 <210> 29 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> ligase recognition motif <400> 29 Lys Val Gly Phe Phe Lys Arg 1 5 <210> 30 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> ligase recognition motif <400> 30 Leu Leu Val Arg Gly Arg Thr Leu Val Val 1 5 10 <210> 31 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> ligase recognition motif <400> 31 Asp Arg His Asp Ser Gly Leu Asp Ser Met 1 5 10 <210> 32 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> ligase recognition motif <220> <221> MISC_FEATURE <222> (2) <223> Xaa can be any naturally occurring amino acid <220> <221> MISC_FEATURE <222> (4) <223> Xaa can be any naturally occurring amino acid <220> <221> MISC_FEATURE <222> (6) <223> Xaa can be any naturally occurring amino acid <400> 32 Pro Xaa Ala Xaa Val Xaa Pro 1 5 <210> 33 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> ligase recognition motif <220> <221> MISC_FEATURE <222> (3) <223> Xaa can be any naturally occurring amino acid <220> <221> MISC_FEATURE <222> (5)..(6) <223> Xaa can be any naturally occurring amino acid <400> 33 Pro Pro Xaa Tyr Xaa Xaa Met 1 5 <210> 34 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> ligase recognition motif <220> <221> MISC_FEATURE <222> (3) <223> Xaa can be any naturally occurring amino acid <220> <221> MISC_FEATURE <222> (5) <223> Xaa can be any naturally occurring amino acid <400> 34 Pro Pro Xaa Tyr Xaa 1 5

Claims (11)

  1. 피험자에서 생물학적 효과의 감소된 기간을 나타내는 보툴리눔 (Clostridium botulinum) 신경독 (BoNT/E) 폴리펩티드를 인코딩하는 변형 폴리뉴클레오티드로서, 상기 신경독 폴리펩티드는 신경독 폴리펩티드의 경쇄 내에 하나 이상의 분해 신호를 포함하며, 여기서 상기 신경독 폴리펩티드의 경쇄 내에 분해 신호는 다음으로부터 선택되는 변형 폴리뉴클레오티드:
    a) 경쇄의 내부 또는 말단에 도입된 PEST 모티프;
    b) 경쇄의 내부 또는 말단에 도입된 E3 리가아제 인식 모티프.
  2. 청구항 1에 있어서,
    상기 생물학적 효과는 피험자에서 근육 마비를 일으키는 변형 폴리뉴클레오티드.
  3. 청구항 1에 있어서,
    피험자에서 생물학적 효과의 기간은 4, 3 또는 2주 미만 동안 지속하는, 변형 폴리뉴클레오티드.
  4. 청구항 1에 있어서,
    상기 신경독 폴리펩티드는 SEQ ID NO: 9에 나타낸 바와 같은 뉴클레오티드 서열을 갖는 핵산 서열에 의해 인코딩되는, 변형 폴리뉴클레오티드.
  5. 청구항 1의 폴리뉴클레오티드를 포함하는 벡터.
  6. 청구항 1의 폴리뉴클레오티드를 포함하는 숙주 세포.
  7. 청구항 6에 있어서,
    상기 세포는 E.coli 세포, 클로스트리디움 및 바실러스 세포부터 선택되는 숙주 세포.
  8. 청구항 5의 벡터를 포함하는 숙주 세포.
  9. 청구항 8에 있어서,
    상기 세포는 E.coli 세포, 클로스트리디움 및 바실러스 세포로부터 선택되는 숙주 세포.
  10. a) 신경독 폴리펩티드를 발현시키는 조건하에서 청구항 6의 숙주 세포를 배양하는 단계; 및
    b) 단계 a)의 배양된 숙주 세포로부터 신경독 폴리펩티드를 얻는 단계를 포함하는, 피험자에서 생물학적 효과의 감소된 기간을 나타내는 신경독 폴리펩티드의 제조방법.
  11. 청구항 10에 있어서,
    상기 방법은, 상기 신경독 폴리펩티드를 하나 이상의 약학적으로 허용가능한 담체를 포함하는 약제로서 제형화하는 단계를 더욱 포함하는, 신경독 폴리펩티드의 제조방법.
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