HRP20120336T1 - Receptori vezani na mutacije g-proteina i metode njihovog odabira - Google Patents
Receptori vezani na mutacije g-proteina i metode njihovog odabira Download PDFInfo
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- HRP20120336T1 HRP20120336T1 HRP20120336AT HRP20120336T HRP20120336T1 HR P20120336 T1 HRP20120336 T1 HR P20120336T1 HR P20120336A T HRP20120336A T HR P20120336AT HR P20120336 T HRP20120336 T HR P20120336T HR P20120336 T1 HRP20120336 T1 HR P20120336T1
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- gpcr
- ligand
- mutation
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- conformation
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- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 title claims abstract 38
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 title claims abstract 38
- 238000000034 method Methods 0.000 title claims abstract 29
- 239000003446 ligand Substances 0.000 claims abstract 31
- 230000035772 mutation Effects 0.000 claims abstract 23
- 239000003599 detergent Substances 0.000 claims abstract 3
- 238000010438 heat treatment Methods 0.000 claims abstract 3
- 238000004925 denaturation Methods 0.000 claims abstract 2
- 230000036425 denaturation Effects 0.000 claims abstract 2
- 238000005259 measurement Methods 0.000 claims abstract 2
- 239000000556 agonist Substances 0.000 claims 4
- 239000005557 antagonist Substances 0.000 claims 4
- 102000016359 Fibronectins Human genes 0.000 claims 2
- 108010067306 Fibronectins Proteins 0.000 claims 2
- 108091006027 G proteins Proteins 0.000 claims 2
- 102000030782 GTP binding Human genes 0.000 claims 2
- 108091000058 GTP-Binding Proteins 0.000 claims 2
- 125000000539 amino acid group Chemical group 0.000 claims 2
- 238000002866 fluorescence resonance energy transfer Methods 0.000 claims 2
- 229920001184 polypeptide Polymers 0.000 claims 2
- 102000004196 processed proteins & peptides Human genes 0.000 claims 2
- 108090000765 processed proteins & peptides Proteins 0.000 claims 2
- 102000009346 Adenosine receptors Human genes 0.000 claims 1
- 108050000203 Adenosine receptors Proteins 0.000 claims 1
- 108060003345 Adrenergic Receptor Proteins 0.000 claims 1
- 102000017910 Adrenergic receptor Human genes 0.000 claims 1
- 102000008102 Ankyrins Human genes 0.000 claims 1
- 108010049777 Ankyrins Proteins 0.000 claims 1
- 102000003916 Arrestin Human genes 0.000 claims 1
- 108090000328 Arrestin Proteins 0.000 claims 1
- 102000008924 GPCR kinases Human genes 0.000 claims 1
- 108050000878 GPCR kinases Proteins 0.000 claims 1
- 102000017922 Neurotensin receptor Human genes 0.000 claims 1
- 108060003370 Neurotensin receptor Proteins 0.000 claims 1
- 102000008944 RGS Proteins Human genes 0.000 claims 1
- 108010074020 RGS Proteins Proteins 0.000 claims 1
- 150000001413 amino acids Chemical class 0.000 claims 1
- 239000012634 fragment Substances 0.000 claims 1
- JCVAGGLLUIBFSY-UHFFFAOYSA-H hexasodium 5-[(1,8-dihydroxy-3,6-disulfonatonaphthalen-2-yl)diazenyl]-4-hydroxy-3-[(8-hydroxy-3,6-disulfonatonaphthalen-1-yl)diazenyl]naphthalene-2,7-disulfonate Chemical compound [Na+].[Na+].[Na+].[Na+].[Na+].[Na+].Oc1cc(cc2cc(c(N=Nc3cc(cc4cc(c(N=Nc5cc(cc6cc(cc(O)c56)S([O-])(=O)=O)S([O-])(=O)=O)c(O)c34)S([O-])(=O)=O)S([O-])(=O)=O)c(O)c12)S([O-])(=O)=O)S([O-])(=O)=O JCVAGGLLUIBFSY-UHFFFAOYSA-H 0.000 claims 1
- 229940125425 inverse agonist Drugs 0.000 claims 1
- UMFJAHHVKNCGLG-UHFFFAOYSA-N n-Nitrosodimethylamine Chemical compound CN(C)N=O UMFJAHHVKNCGLG-UHFFFAOYSA-N 0.000 claims 1
- 239000004031 partial agonist Substances 0.000 claims 1
- 102000027426 receptor tyrosine kinases Human genes 0.000 claims 1
- 108091008598 receptor tyrosine kinases Proteins 0.000 claims 1
- 230000002194 synthesizing effect Effects 0.000 claims 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/72—Receptors; Cell surface antigens; Cell surface determinants for hormones
- C07K14/723—G protein coupled receptor, e.g. TSHR-thyrotropin-receptor, LH/hCG receptor, FSH receptor
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/10—Processes for the isolation, preparation or purification of DNA or RNA
- C12N15/102—Mutagenizing nucleic acids
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/10—Processes for the isolation, preparation or purification of DNA or RNA
- C12N15/1034—Isolating an individual clone by screening libraries
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/566—Immunoassay; Biospecific binding assay; Materials therefor using specific carrier or receptor proteins as ligand binding reagents where possible specific carrier or receptor proteins are classified with their target compounds
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
- G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
- G01N2333/72—Assays involving receptors, cell surface antigens or cell surface determinants for hormones
- G01N2333/726—G protein coupled receptor, e.g. TSHR-thyrotropin-receptor, LH/hCG receptor, FSH
Abstract
Metoda za odabir receptora vezanog na G-proteine (GPCR) s većom konformacijskom stabilnosti, metoda naznačena time da obuhvaća (a) osiguranje mutacije ili više mutacija izvornog GPCR-a, (b) odabir liganda iz određene skupine, s tim da se taj ligand mora vezati na izvorni GPCR kada se GPCR nalazi u određenoj konformaciji. (c) određivanje je li ta ili svaka mutacija GPCR-a povećala konformacijsku stabilnost u odnosu na vezanje odabranog liganda u usporedbi s konformacijskom stabilnosti izvornog GPCR-a u odnosu na sposobnost vezanja tog liganda, i to na temelju mjerenja denaturacije koja se očituje gubitkom sposobnosti vezanja liganada, pod uvjetima denaturacije kao što su zagrijavanje, deterdžent, kaotrop ili ekstremni pH, te (d) odabir onih mutacija koje imaju povećanu konformacijsku stabilnost u usporedbi s izvornim GPCR-om u odnosu na vezanje odabranog liganda; s tim da određena konformacija u kojoj se GPCR nalazi iz koraka (c) odgovara istoj kategoriji liganda kao što je ligand odabran prema koraku (b). Patent sadrži još 21 patentni zahtjev.
Claims (22)
1. Metoda za odabir receptora vezanog na G-proteine (GPCR) s većom konformacijskom stabilnosti, metoda naznačena time da obuhvaća
(a) osiguranje mutacije ili više mutacija izvornog GPCR-a,
(b) odabir liganda iz određene skupine, s tim da se taj ligand mora vezati na izvorni GPCR kada se GPCR nalazi u određenoj konformaciji.
(c) određivanje je li ta ili svaka mutacija GPCR-a povećala konformacijsku stabilnost u odnosu na vezanje odabranog liganda u usporedbi s konformacijskom stabilnosti izvornog GPCR-a u odnosu na sposobnost vezanja tog liganda, i to na temelju mjerenja denaturacije koja se očituje gubitkom sposobnosti vezanja liganada, pod uvjetima denaturacije kao što su zagrijavanje, deterdžent, kaotrop ili ekstremni pH, te
(d) odabir onih mutacija koje imaju povećanu konformacijsku stabilnost u usporedbi s izvornim GPCR-om u odnosu na vezanje odabranog liganda; s tim da određena konformacija u kojoj se GPCR nalazi iz koraka (c) odgovara istoj kategoriji liganda kao što je ligand odabran prema koraku (b).
2. Metoda iz Zahtjeva 1 naznačena time da se jedna mutacija ili više mutacija dovode u kontakt s odabranim ligandom prije koraka (c).
3. Metoda iz Zahtjeva 1 ili 2 naznačena time da su jedna mutacija ili više mutacija dostupne u solubiliziranom obliku.
4. Metoda iz Zahtjeva 1-3 naznačena time da je odabrani ligand iz skupine agonista, a određena konformacija je konformacija agonista ili je odabrani ligand iz skupine antagonista i određena konformacija je konformacija antagonista.
5. Metoda iz Zahtjeva 4 naznačena time da je odabrani ligand iz skupine antagonista i određena konformacija u kojoj se GPCR nalazi iz koraka (c) je konformacija agonista.
6. Metoda iz Zahtjeva 1-5 naznačena time da je sklonost vezanju mutacije na odabrani ligand u bitnome jednaka ili veća od sklonosti vezanju izvora na odabrani ligand.
7. Metoda iz Zahtjeva 1-6 naznačena time da se metoda ponavlja u jednom ili nekoliko krugova, s tim da odabrana mutacija s povećanom konformacijskom stabilnosti iz koraka (a) koji predstavljaju izvorni GPCR u naknadnom krugu metode.
8. Metoda iz Zahtjeva 1-7 naznačena time da se odabire mutacija GPCR-a koja ima povećanu stabilnost prema zagrijavanju, deterdžentu, kaotropu i ekstremnom pH.
9. Metoda iz Zahtjeva 8 naznačena time da se odabire mutacija GPCR-a s povećanom termostabilnosti.
10. Metoda iz Zahtjeva 1-9 naznačena time da je ligand potpuni agonist, djelomični agonist, obrnuti agonist ili antagonist.
11. Metoda iz Zahtjeva 1-10 naznačena time da je ligand polipeptid koji se vezuje na GPCR.
12. Metoda iz Zahtjeva 11 naznačena time da je polipeptid antitijelo, ankirin, G-protein, RGS protein, arestin, GPCR kinaza, receptorske tirozin-kinaze, RAMP, NFS, GPCR, podjedinica NDMA receptora NR1 i NR2 ili kalcion (eng. calcyon), struktura fibronektinske domene (eng. fibronectin domain framework) ili njihov fragment ili derivat koji se veže na GPCR.
13. Metoda iz Zahtjeva 1-12 naznačena time da se u koraku (b) odabiru jedan ili više liganada, a prisutnost svakoga ima za posljedicu da se GPCR nalazi u istoj određenoj konformaciji.
14. Metoda sukladno bilo kojem od prethodnih zahtjeva naznačena time da se odabire mutacija GPCR-a koja ima smanjenu sposobnost vezanja liganda koji je u drugačijoj skupini od one u kojoj je ligand koji je odabran u koraku (b) u usporedbi sa svojom maticom.
15. Metoda sukladno bilo kojem od prethodnih zahtjeva naznačena time da je GPCR®-adrenergični receptor, adenozinski receptor ili neurotenzinski receptor.
16. Metoda iz Zahtjeva 1-15 naznačena time da se ligand označava na način da može biti identificiran.
17. Metoda iz Zahtjeva 16 naznačena time da je ligand fluorescentno označen.
18. Metoda iz Zahtjeva 1-15 naznačena time da korak (c) obuhvaća primjenu rezonantnog prijenosa energije fluorescencije (FRET).
19. Metoda za pripremu mutacije GPCR-a, naznačena time da obuhvaća:
a) provođenje metode iz bilo kojeg zahtjeva od 1 do 18,
b) utvrđivanje pozicije ili više pozicija ostatka ili ostataka mutirane aminokiseline u mutaciji GPCR-a ili više GPCR-a koji su odabrani zbog povećane konformacijske stabilnosti, i
c) sintetiziranje mutacije GPCR-a koja sadrži zamjensku aminokiselinu na jednoj ili više utvrđenih pozicija.
20. Metoda u skladu sa Zahtjevom 19 naznačena time da mutacija GPCR-a sadrži više mutacija u usporedbi s izvornim GPCR-om.
21. Metoda u skladu sa Zahtjevima 1-19 naznačena time da se utvrđuje je li odabrana ili pripremljena mutacija GPCR-a sposobna povezati se s G-proteinom.
22. Metoda u skladu sa Zahtjevima 1-19 naznačena time da se utvrđuje je li odabrana ili pripremljena mutacija GPCR-a sposobna vezati veći broj liganada iste skupine kao što je odabrani ligand koji se na usporediv način rasprostire i/ili ima jednaki red sklonosti kao i izvorni GPCR.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0705450A GB0705450D0 (en) | 2007-03-22 | 2007-03-22 | Mutant proteins and method for selecting them |
| GB0724052A GB0724052D0 (en) | 2007-12-08 | 2007-12-08 | Mutant proteins and methods for selecting them |
| PCT/GB2008/000986 WO2008114020A2 (en) | 2007-03-22 | 2008-03-20 | Mutant g-protein coupled receptors and methods for selecting them |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HRP20120336T1 true HRP20120336T1 (hr) | 2012-05-31 |
Family
ID=39386585
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HRP20120336AT HRP20120336T1 (hr) | 2007-03-22 | 2012-04-16 | Receptori vezani na mutacije g-proteina i metode njihovog odabira |
Country Status (14)
| Country | Link |
|---|---|
| US (7) | US8785135B2 (hr) |
| EP (4) | EP2386635A3 (hr) |
| JP (6) | JP4842400B2 (hr) |
| CN (2) | CN103641908A (hr) |
| AT (1) | ATE544854T1 (hr) |
| AU (1) | AU2008228085B2 (hr) |
| CA (1) | CA2681415C (hr) |
| DK (1) | DK2121919T3 (hr) |
| ES (1) | ES2381780T3 (hr) |
| GB (4) | GB2456237B8 (hr) |
| HR (1) | HRP20120336T1 (hr) |
| PL (1) | PL2121919T3 (hr) |
| PT (1) | PT2121919E (hr) |
| WO (1) | WO2008114020A2 (hr) |
Families Citing this family (28)
| Publication number | Priority date | Publication date | Assignee | Title |
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| ATE544854T1 (de) * | 2007-03-22 | 2012-02-15 | Heptares Therapeutics Ltd | Mutante g-protein-gekoppelte rezeptoren und selektionsverfahren dafür |
| GB0724051D0 (en) * | 2007-12-08 | 2008-01-16 | Medical Res Council | Mutant proteins and methods for producing them |
| GB0724860D0 (en) * | 2007-12-20 | 2008-01-30 | Heptares Therapeutics Ltd | Screening |
| GB0802474D0 (en) * | 2008-02-11 | 2008-03-19 | Heptares Therapeutics Ltd | Mutant proteins and methods for selecting them |
| DE08718604T1 (de) * | 2008-03-05 | 2009-12-24 | Medical Research Council | Kristallstruktur |
| GB0910725D0 (en) | 2009-06-22 | 2009-08-05 | Heptares Therapeutics Ltd | Mutant proteins and methods for producing them |
| GB201014715D0 (en) | 2010-09-06 | 2010-10-20 | Vib Vzw | Nanobodies stabilizing functional conformational states of GPCRS |
| EP2606062A2 (en) | 2010-08-20 | 2013-06-26 | Heptares Therapeutics Limited | Biological materials and uses thereof |
| WO2012098413A1 (en) * | 2011-01-21 | 2012-07-26 | Heptares Therapeutics Limited | Mutant g-protein coupled receptor proteins and methods for producing them |
| KR101963914B1 (ko) | 2011-02-23 | 2019-03-29 | 매사추세츠 인스티튜트 오브 테크놀로지 | 수용성 막 단백질 및 이의 제조 방법 및 이의 사용 방법 |
| WO2012120315A2 (en) | 2011-03-10 | 2012-09-13 | Heptares Therapeutics Limited | Mutant proteins and methods for producing them |
| WO2013021206A2 (en) | 2011-08-10 | 2013-02-14 | Heptares Therapeutics Limited | Stable proteins |
| ES2676827T3 (es) * | 2012-06-01 | 2018-07-25 | Heptares Therapeutics Limited | Ensayos |
| DK2951201T3 (en) | 2013-01-30 | 2018-01-08 | Vib Vzw | Novel chimeric polypeptides for screening and drug detection purposes |
| WO2014140586A2 (en) | 2013-03-15 | 2014-09-18 | Medical Research Council | Mutant proteins and methods for their production |
| US9670264B2 (en) | 2013-04-25 | 2017-06-06 | The Trustees Of The University Of Pennsylvania | Water soluble G-protein coupled receptor |
| EP2989440A4 (en) | 2013-04-25 | 2017-01-04 | The Trustees Of The University Of Pennsylvania | Opioid detection based on high quality graphene transistor arrays and a synthetic mu receptor |
| CN105593240A (zh) * | 2013-06-11 | 2016-05-18 | 保罗·谢勒学院 | 用于以单氨基酸分辨率确定可突变配体-gpcr结合的方法以及突变配体和gpcr对 |
| US10373702B2 (en) | 2014-03-27 | 2019-08-06 | Massachusetts Institute Of Technology | Water-soluble trans-membrane proteins and methods for the preparation and use thereof |
| CN104151401A (zh) * | 2014-06-05 | 2014-11-19 | 维亚生物科技(上海)有限公司 | 融合表达离子通道蛋白及运输蛋白的方法及其使用的蛋白片断 |
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