CN113501876A - 一种特异性结合蛋白激酶p38δ的纳米抗体、核酸、表达载体、宿主细胞及其应用 - Google Patents
一种特异性结合蛋白激酶p38δ的纳米抗体、核酸、表达载体、宿主细胞及其应用 Download PDFInfo
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Abstract
本发明提供了一种特异性结合蛋白激酶p38δ的纳米抗体、核酸、表达载体、宿主细胞及其应用，所述纳米抗体具有至少一种以下所示的互补决定区：如SEQ ID NO.1所示氨基酸序列的互补决定区CDR1；如SEQ ID NO.2所示氨基酸序列的互补决定区CDR2；和如SEQ ID NO.3所示氨基酸序列的互补决定区CDR3。此纳米抗体具有针对蛋白激酶p38δ独特的抗原互补决定区，对蛋白激酶p38δ显示出了高度特异的结合活性，且不与p38MAPK的其他家族蛋白p38α、p38γ和p38δ发生交叉反应。同时本申请的纳米抗体具有突出的热稳定性和酸碱稳定性。
Description
技术领域
本发明涉及生物技术领域，且特别涉及一种特异性结合蛋白激酶p38δ的纳米抗体、核酸、表达载体、宿主细胞及其应用。
背景技术
p38δ是p38 MAPK家族中的一种丝氨酸/苏氨酸特异性蛋白激酶，主要参与调控细胞外刺激与细胞内应答之间的信号转导。p38 MAPK家族共有四个成员，即p38α、p38β、p38γ以及p38δ。虽然所有的p38 MAPKs在序列及结构上都高度保守，但是他们在生理和病理环境中的功能却不尽相同。其中，p38α和p38β广泛表达于各种细胞和组织，调控细胞的基本生命活动。例如：p38α在白细胞、肝、脾、小脑、骨髓、甲状腺及胎盘中具有较高的表达水平；p38β主要在脑和心脏中进行表达。而p38γ和p38δ的表达具有组织细胞特异性，并受严格的调控，p38γ主要在骨骼肌中表达；p38δ的表达主要在肺、肾、肠、唾液腺的表皮细胞及睾丸、卵巢、肾上腺和垂体。近年来研究揭示，p38δ在多种疾病的发生发展中发挥重要的调控功能，如糖尿病、免疫疾病、神经退行性疾病、癌症等。p38δ是潜在的疾病诊断生物标志物及治疗靶点。在药物研发方面，由于p38 MAPKs蛋白间高度保守，开发不与其他p38 MAPK蛋白交叉反应的p38δ特异性抑制剂较为困难，因此至今尚无有效的p38δ抑制剂。
纳米抗体是源于重链抗体可变区域的小分子抗体，其分子量约为15kDa，具有亲和力高、稳定性强、组织相容性好以及易筛选、易制备等特点，近年来在治疗型药物抗体、临床检测型抗体、科研运用型抗体等方面得到了广泛的研究与发展。纳米抗体主要是由4个保守的骨架区(FR)和3个抗原互补决定区(CDR)依次交叉串联形成，其中，抗原互补决定区(CDR)是抗原识别及抗原结合的主要执行部位。所以纳米抗体的筛选关键在于获得可以介导与抗原特异性结合的互补决定区。纳米抗体中的互补决定区根据其在整个抗体中的位置不同，可以依次分为三个独立区域，即互补决定区1(CDR1)、互补决定区2(CDR2)和互补决定区3(CDR3)。与传统抗体相比，纳米抗体互补决定区的氨基酸序列较长，使得其可以深入抗原较为隐匿的结构中与其相互作用。纳米抗体还具有良好的热稳定性和酸碱稳定性，这为其在检测、治疗等领域的应用提供了传统抗体所无法比拟的优越性。因此，若提供一种能够特异性结合蛋白激酶p38δ的纳米抗体，对于以p38δ为生物标志物和治疗靶点的疾病诊断、治疗提供了新的思路和研究方向。
发明内容
本发明的第一目的在于提供一种特异性结合蛋白激酶p38δ的纳米抗体，此纳米抗体具有针对蛋白激酶p38δ独特的抗原互补决定区，对蛋白激酶p38δ显示出了高度特异的结合活性，且不与p38 MAPK的其他家族蛋白p38α、p38β和p38δ发生交叉反应。同时本申请的纳米抗体具有突出的热稳定性和酸碱稳定性。
本发明的第二目的在于提供编码所述的特异性结合蛋白激酶p38δ的纳米抗体的核酸。
本发明的第三目的在于提供含有所述的特异性结合蛋白激酶p38δ的纳米抗体的核酸的表达载体。
本发明的第四目的在于提供含有所述的表达载体的宿主细胞。
本发明的第五目的在于提供特异性结合蛋白激酶p38δ的纳米抗体在制备用于检测蛋白激酶p38δ的试剂盒中的应用。
本发明的第六目的在于提供特异性结合蛋白激酶p38δ的纳米抗体在制备治疗或预防与蛋白激酶p38δ调控作用相关的疾病药物中的应用。
本发明解决其技术问题是采用以下技术方案来实现的。
本发明提出一种特异性结合蛋白激酶p38δ的纳米抗体，所述纳米抗体具有至少一种以下所示的互补决定区：如SEQ ID NO.1所示氨基酸序列的互补决定区CDR1；如SEQ IDNO.2所示氨基酸序列的互补决定区CDR2；和如SEQ ID NO.3所示氨基酸序列的互补决定区CDR3。
根据一种优选实施方式，所述纳米抗体具有如SEQ ID NO.7所示的氨基酸序列。
本发明还提供了一种编码所述的特异性结合蛋白激酶p38δ的纳米抗体的核酸，所述核酸能够编码至少一种以下所示的氨基酸序列：如SEQ ID NO.1所示氨基酸序列；如SEQID NO.2所示氨基酸序列；和如SEQ ID NO.3所示氨基酸序列。
根据一种优选实施方式，所述核酸具有至少一种以下所示的编码序列：如SEQ IDNO.4所示的编码序列；如SEQ ID NO.5所示的编码序列；和如SEQ ID NO.6所示的编码序列。
根据一种优选实施方式，所述核酸具有如SEQ ID NO.8所示的编码序列。
本发明还提供了一种含有所述的特异性结合蛋白激酶p38δ的纳米抗体的核酸的表达载体，所述表达载体包括原核生物表达载体、真核生物表达载体或体外表达载体系统。
根据一种优选实施方式，所述表达载体为pET22b。
本发明还提供了一种含有所述的表达载体的宿主细胞，所述宿主细胞包括原核生物或真核生物。
本发明还提供了所述的特异性结合蛋白激酶p38δ的纳米抗体在制备用于检测蛋白激酶p38δ的试剂盒中的应用。
本发明还提供了所述的特异性结合蛋白激酶p38δ的纳米抗体在制备治疗或预防与蛋白激酶p38δ调控作用相关的疾病药物中的应用。
基于上述技术方案，本发明的特异性结合蛋白激酶p38δ的纳米抗体、核酸、表达载体、宿主细胞及其应用至少具有如下技术效果：
本发明特异性结合蛋白激酶p38δ的纳米抗体具有至少一种以下所示的互补决定区：如SEQ ID NO.1所示氨基酸序列的互补决定区CDR1；如SEQ ID NO.2所示氨基酸序列的互补决定区CDR2；和如SEQ ID NO.3所示氨基酸序列的互补决定区CDR3。使得该纳米抗体具有针对蛋白激酶p38δ独特的抗原互补决定区，对蛋白激酶p38δ显示出了高度特异的结合活性，且不与p38 MAPK的其他家族蛋白p38α、p38β和p38γ发生交叉反应。同时本申请的纳米抗体具有突出的热稳定性和酸碱稳定性。为检测蛋白激酶p38δ以及治疗与蛋白激酶p38δ调控作用相关的疾病提供了新方向。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案，下面将对实施例或现有技术描述中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图仅仅是本发明的一些实施例，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据这些附图获得其他的附图。
图1为本发明实施例1中p38γ和p38δ的表达与纯化的示意图，其中图1A示出了表达载体pET28a-p38γ/p38δ-2×Strep主要元件组成；图1B示出了含有重组质粒pET28a-p38γ/p38δ-2×Strep的表达菌株诱导表达蛋白并用MagStrep“type3”XT磁珠纯化，SDS-PAGE蛋白电泳分析表达及纯化产物；
图2为本发明实施例2中Nb13-1稳定结合p38δ的示意图，其中图2A示出了纳米抗体表达载体pET22b-NB-FLAG主要元件组成；Control Nb为含有相同骨架序列的对照纳米抗体；图2B示出了ELISA检测含有纳米抗体表达载体的大肠杆菌细胞周至提取物与p38δ及对照抗原BSA的结合情况；图2C示出了免疫荧光染色检测纳米抗体Nb13-1与p38δ的结合情况；图2D示出了间接ELISA方法测定纳米抗体Nb13-1与p38δ的解离常数KD；
图3为本发明实施例3中Nb13-1不与p38MAPK家族其他蛋白交叉反应情况，其中图3A示出了ELISA检测Nb13-1与p38 MAPK家族蛋白间的交叉反应情况；图3B示出了免疫共沉淀检测的Nb13-1与p38 MAPK家族蛋白间的交叉反应情况；
图4为本发明实施例4中免疫共沉淀检测不同温度、不同酸碱环境处理后的Nb13-1的p38δ结合能力。
具体实施方式
为使本发明的目的、技术方案和优点更加清楚，下面将对本发明的技术方案进行详细的描述。显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动的前提下所得到的所有其它实施方式，都属于本发明所保护的范围。
下面结合具体实施例对本发明的特异性结合蛋白激酶p38δ的纳米抗体及其应用进行具体说明。所举实例只用于解释和理解本发明，并非用于限定本发明的范围。
本发明提出的一种特异性结合蛋白激酶p38δ的纳米抗体，所述的纳米抗体具有至少一种以下所示的互补决定区：如SEQ ID NO.1所示氨基酸序列的互补决定区CDR1；如SEQID NO.2所示氨基酸序列的互补决定区CDR2；和如SEQ ID NO.3所示氨基酸序列的互补决定区CDR3。可以理解为：本发明的纳米抗体具有三个互补决定区CDR1、CDR2和CDR3，且三个互补决定区中至少一种互补决定区满足：互补决定区CDR1具有如SEQ ID NO.1所示氨基酸序列；互补决定区CDR2具有如SEQ ID NO.2所示氨基酸序列；或者互补决定区CDR3具有如SEQID NO.3所示氨基酸序列。从而使得纳米抗体形成具有针对蛋白激酶p38δ独特的抗原互补决定区，对蛋白激酶p38δ显示出了高度特异的结合活性，且不与p38 MAPK的其他家族蛋白p38α、p38β和p38γ发生交叉反应。
进一步优选的，本发明还提供了一种编码上述特异性结合蛋白激酶p38δ的纳米抗体的核酸，所述核酸能够编码至少一种以下所示的氨基酸序列：如SEQ ID NO.1所示氨基酸序列；如SEQ ID NO.2所示氨基酸序列；和如SEQ ID NO.3所示氨基酸序列。优选的，所述核酸具有至少一种以下所示的编码序列：如SEQ ID NO.4所示的编码序列；如SEQ ID NO.5所示的编码序列；和如SEQ ID NO.6所示的编码序列。以便能够编码本发明的特异性结合蛋白激酶p38δ的纳米抗体的至少一种互补决定区。
进一步优选的，本发明还提供了一种含有所述的特异性结合蛋白激酶p38δ的纳米抗体的核酸的表达载体，所述表达载体包括原核生物表达载体、真核生物表达载体或体外表达载体系统。优选的，所述表达载体为pET22b。
进一步优选的，本发明还提供了一种含有所述的表达载体的宿主细胞，所述宿主细胞包括原核生物或真核生物。也可采用其他包含所述表达载体的体外表达系统。
进一步优选的，本发明还提供了所述的特异性结合蛋白激酶p38δ的纳米抗体在制备用于检测蛋白激酶p38δ的检测试剂盒中的应用。
进一步优选的，本发明还提供了所述的特异性结合蛋白激酶p38δ的纳米抗体在制备治疗或预防与蛋白激酶p38δ调控作用相关的疾病药物中的应用。
以下结合实施例对本发明的特征和性能作进一步的详细描述。
实施例1
本实施例1提供了对特异性结合蛋白激酶p38δ的纳米抗体的筛选。具体步骤如下：
(1)依据IBA公司所开发的第三代
蛋白纯化系统构建p38δ、p38γ表达载体，如图1A。其中p38δ氨基酸序列如SEQ ID NO.9所示，p38γ氨基酸序列如SEQ ID NO.10所示；p38δDNA编码序列如SEQ ID NO.11所示，p38γDNA编码序列如SEQ ID NO.12所示。2×Strep标签氨基酸序列如SEQ ID NO.13所示，2×Strep标签DNA编码序列如SEQ ID NO.14所示。将构建好的表达载体转化至大肠杆菌表达细菌BL21(DE3)中，通过IPTG诱导其表达，利用MagStrep“type3”XT磁珠进行蛋白纯化，利用SDS-PAGE及考马斯亮蓝染色检测表达及纯化产物，最终获得高纯度p38δ和p38γ蛋白，见图1B。
(2)将纯化所得p38δ和p38γ蛋白分别包被至磁珠；将纳米抗体噬菌体文库稀释至含2.5％BSA TBST溶液中；然后将纳米抗体文库(文库构构建见如下文献：Wang,Wenyi,etal."Identification of nanobodies against hepatocellular carcinoma markerglypican-3."Molecular Immunology 131(2021):13-22.)与p38γ包被磁珠室温孵育1小时，以去除非特异性结合噬菌体；孵育后弃去磁珠，将噬菌体文库溶液再次与p38δ包被磁珠室温孵育2小时，然后弃去噬菌体溶液，TBST洗涤磁珠20次，PBS洗涤磁珠10次，然后用100μL洗脱液(Triethylamine,0.1M)孵育磁珠10min，最后再用100μL 1M Tris-HCl溶液中和洗脱液。将洗脱液加入1ml大肠杆菌SS320，37℃孵育30min，利用辅助噬菌体M13K07扩增噬菌体，最后收集纯化噬菌体并用于下一轮筛选。
(3)完成第三轮筛选噬菌体侵染后，将大肠杆菌SS320涂平板，挑取40个含噬菌体质粒的单克隆进行测序。根据测序结果，选取重复率较高的单克隆，进行纳米抗体表达及鉴定。
实施例2
本实施例提供了对纳米抗体进行鉴定的方法。
(1)选取实施例1中所获克隆Nb13-1，其DNA序列如SEQ ID NO.8，其编码的氨基酸序列如SEQ ID NO.7所示。通过分子克隆将编码纳米抗体的核苷酸序列亚克隆至表达载体pET22b中，并于其C端融合FLAG标签序列，如图2A所示，并以同样方法构建对照纳米抗体表达载体。
(2)将所构建纳米抗体表达载体转化至大肠杆菌表达菌株BL21(DE3)中，通过IPTG诱导表达，然后利用低渗发提取细菌细胞周至蛋白。
(3)ELISA检测表达纳米抗体细菌细胞周至蛋白与p38δ的结合：
将p38δ和BSA蛋白包被至96孔酶标板，封闭液封闭后，纳米抗体细菌细胞周至提取物37℃孵育2小时，然后抗FALG鼠单克隆抗体37℃孵育1小时，然后HRP标记的鼠二抗37℃孵育1小时，根据ELISA试剂盒(索莱宝)进行显色反应及终止反应，最终检测反应溶液的450nM吸光值(OD450)。如图2B，结果分析显示，Nb13-1特异性结合p38δ。
(4)免疫荧光染色检测纳米抗体Nb13-1与p38δ的结合：
HeLa细胞中利用瞬时转染过表达Myc-p38δ，24小时后，4％多聚甲醛固定细胞15分钟，然后0.2％Triton-X100 PBS溶液通透10分钟，然后封闭液封闭1小时，anti-Myc鼠抗孵育1小时，对照纳米抗体或Nb13-1稀释液孵育2小时，anti-FLAG兔抗孵育1小时，然后AlexaFlour 594偶联兔二抗和Alexa Flour 488偶联鼠二抗孵育1小时。最后DAPI稀释液孵育细胞5分钟，封片后，显微镜观察拍照。如图2C所示，结果显示，与对照纳米抗体相比，Nb13-1可以成功标记p38δ见图2C。
(5)间接ELISA方法测定纳米抗体Nb13-1与p38δ的解离常数KD：
将p38δ和BSA蛋白包被至96孔酶标板，封闭液封闭后，将纳米抗体分别以0μM、0.1μM、0.2μM、0.4μM、0.8μM、1.6μM、3.2μM、6.4μM的浓度37℃孵育抗原2小时，然后抗FALG鼠单克隆抗体37℃孵育1小时，然后HRP标记的鼠二抗37℃孵育1小时，根据ELISA试剂盒(索莱宝公司)进行显色反应及终止反应，最终检测反应溶液的450nM吸光值(OD450)，利用GraphpadPrism软件拟合4参数曲线，并计算解离常数KD。如图2D，结果分析显示，Nb13-1与p38δ的解离常数KD＝(1.32±0.61)×10-6M。
实施例3
本实施例3针对Nb13-1与p38 MAPK其它家族蛋白的交叉反应进行了检测。
(1)ELISA检测Nb13-1与p38 MAPK其它家族蛋白的交叉反应：将p38α、p38β、p38γ及p38δ蛋白包被至96孔酶标板，封闭液封闭后，纳米抗体细菌细胞周至提取物37℃孵育2小时，然后抗FALG鼠单克隆抗体37℃孵育1小时，然后HRP标记的鼠二抗37℃孵育1小时，根据ELISA试剂盒(索莱宝)进行显色反应及终止反应，最终检测反应溶液的450nM吸光值(OD450)，如图3A所示，结果分析显示，Nb13-1特异性结合p38δ，不与p38α、p38β、p38γ交叉反应。
(2)免疫共沉淀检测Nb13-1与p38 MAPK其它家族蛋白的交叉反应：纳米抗体细菌细胞周至提取物与p38α、p38β、p38γ及p38δ表达细菌裂解液4℃共孵育2小时，然后加入10μL anti-FLAG磁珠4℃再孵育1小时，TBST洗涤磁珠3次后，SDS-PAGE和考马斯亮蓝染色检测免疫共沉淀结果。如图3B所示，结果显示，Nb13-1特异性共沉淀p38δ，不与p38α、p38β、p38γ交叉反应。
实施例4
本实施例对纳米抗体Nb13-1的热稳定性和酸碱稳定性进行了检测。
(1)将纳米抗体Nb13-1分别在4℃、18℃、37℃、42℃、65℃、90℃环境孵育1小时，然后再将其与p38δ表达细菌裂解液4℃共孵育2小时，之后加入10μL anti-FLAG磁珠4℃再孵育1小时，TBST洗涤磁珠3次后，SDS-PAGE和考马斯亮蓝染色检测免疫共沉淀结果。如图4所示，结果显示，37℃、42℃、65℃、90℃处理后的Nb13-1仍然具有良好的p38δ结合能力。
(2)将纳米抗体Nb13-1分别在pH值为2、4、7、10、12的TBS缓冲液中孵育1小时，然后再将其与p38δ表达细菌裂解液4℃共孵育2小时，之后加入10μL anti-FLAG磁珠4℃再孵育1小时，TBST洗涤磁珠3次后，SDS-PAGE和考马斯亮蓝染色检测免疫共沉淀结果。结果显示，pH值为2、12的缓冲液处理Nb13-1之后，纳米抗体Nb13-1仍然具有良好的p38δ结合能力(见图4)。
综上所述，本发明的特异性结合蛋白激酶p38δ的纳米抗体具有针对蛋白激酶p38δ独特的抗原互补决定区，对蛋白激酶p38δ显示出了高度特异的结合活性，且不与p38 MAPK的其他家族蛋白p38α、p38β和p38δ发生交叉反应。
以上所述，仅为本发明的具体实施方式，但本发明的保护范围并不局限于此，任何熟悉本技术领域的技术人员在本发明揭露的技术范围内，可轻易想到变化或替换，都应涵盖在本发明的保护范围之内。
序列表
<110> 四川大学华西医院
<120> 一种特异性结合蛋白激酶p38δ的纳米抗体、核酸、表达载体、宿主细胞及其应用
<141> 2021-07-16
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Phe Ala Lys Arg Ala Tyr Arg Glu Leu Leu Leu Leu Lys His Met Gln
65 70 75 80
His Glu Asn Val Ile Gly Leu Leu Asp Val Phe Thr Pro Ala Ser Ser
85 90 95
Leu Arg Asn Phe Tyr Asp Phe Tyr Leu Val Met Pro Phe Met Gln Thr
100 105 110
Asp Leu Gln Lys Ile Met Gly Met Glu Phe Ser Glu Glu Lys Ile Gln
115 120 125
Tyr Leu Val Tyr Gln Met Leu Lys Gly Leu Lys Tyr Ile His Ser Ala
130 135 140
Gly Val Val His Arg Asp Leu Lys Pro Gly Asn Leu Ala Val Asn Glu
145 150 155 160
Asp Cys Glu Leu Lys Ile Leu Asp Phe Gly Leu Ala Arg His Ala Asp
165 170 175
Ala Glu Met Thr Gly Tyr Val Val Thr Arg Trp Tyr Arg Ala Pro Glu
180 185 190
Val Ile Leu Ser Trp Met His Tyr Asn Gln Thr Val Asp Ile Trp Ser
195 200 205
Val Gly Cys Ile Met Ala Glu Met Leu Thr Gly Lys Thr Leu Phe Lys
210 215 220
Gly Lys Asp Tyr Leu Asp Gln Leu Thr Gln Ile Leu Lys Val Thr Gly
225 230 235 240
Val Pro Gly Thr Glu Phe Val Gln Lys Leu Asn Asp Lys Ala Ala Lys
245 250 255
Ser Tyr Ile Gln Ser Leu Pro Gln Thr Pro Arg Lys Asp Phe Thr Gln
260 265 270
Leu Phe Pro Arg Ala Ser Pro Gln Ala Ala Asp Leu Leu Glu Lys Met
275 280 285
Leu Glu Leu Asp Val Asp Lys Arg Leu Thr Ala Ala Gln Ala Leu Thr
290 295 300
His Pro Phe Phe Glu Pro Phe Arg Asp Pro Glu Glu Glu Thr Glu Ala
305 310 315 320
Gln Gln Pro Phe Asp Asp Ser Leu Glu His Glu Lys Leu Thr Val Asp
325 330 335
Glu Trp Lys Gln His Ile Tyr Lys Glu Ile Val Asn Phe Ser Pro Ile
340 345 350
Ala Arg Lys Asp Ser Arg Arg Arg Ser Gly Met Lys Leu
355 360 365
<210> 10
<211> 367
<212> PRT
<213> Homo sapiens
<400> 10
Met Ser Ser Pro Pro Pro Ala Arg Ser Gly Phe Tyr Arg Gln Glu Val
1 5 10 15
Thr Lys Thr Ala Trp Glu Val Arg Ala Val Tyr Arg Asp Leu Gln Pro
20 25 30
Val Gly Ser Gly Ala Tyr Gly Ala Val Cys Ser Ala Val Asp Gly Arg
35 40 45
Thr Gly Ala Lys Val Ala Ile Lys Lys Leu Tyr Arg Pro Phe Gln Ser
50 55 60
Glu Leu Phe Ala Lys Arg Ala Tyr Arg Glu Leu Arg Leu Leu Lys His
65 70 75 80
Met Arg His Glu Asn Val Ile Gly Leu Leu Asp Val Phe Thr Pro Asp
85 90 95
Glu Thr Leu Asp Asp Phe Thr Asp Phe Tyr Leu Val Met Pro Phe Met
100 105 110
Gly Thr Asp Leu Gly Lys Leu Met Lys His Glu Lys Leu Gly Glu Asp
115 120 125
Arg Ile Gln Phe Leu Val Tyr Gln Met Leu Lys Gly Leu Arg Tyr Ile
130 135 140
His Ala Ala Gly Ile Ile His Arg Asp Leu Lys Pro Gly Asn Leu Ala
145 150 155 160
Val Asn Glu Asp Cys Glu Leu Lys Ile Leu Asp Phe Gly Leu Ala Arg
165 170 175
Gln Ala Asp Ser Glu Met Thr Gly Tyr Val Val Thr Arg Trp Tyr Arg
180 185 190
Ala Pro Glu Val Ile Leu Asn Trp Met Arg Tyr Thr Gln Thr Val Asp
195 200 205
Ile Trp Ser Val Gly Cys Ile Met Ala Glu Met Ile Thr Gly Lys Thr
210 215 220
Leu Phe Lys Gly Ser Asp His Leu Asp Gln Leu Lys Glu Ile Met Lys
225 230 235 240
Val Thr Gly Thr Pro Pro Ala Glu Phe Val Gln Arg Leu Gln Ser Asp
245 250 255
Glu Ala Lys Asn Tyr Met Lys Gly Leu Pro Glu Leu Glu Lys Lys Asp
260 265 270
Phe Ala Ser Ile Leu Thr Asn Ala Ser Pro Leu Ala Val Asn Leu Leu
275 280 285
Glu Lys Met Leu Val Leu Asp Ala Glu Gln Arg Val Thr Ala Gly Glu
290 295 300
Ala Leu Ala His Pro Tyr Phe Glu Ser Leu His Asp Thr Glu Asp Glu
305 310 315 320
Pro Gln Val Gln Lys Tyr Asp Asp Ser Phe Asp Asp Val Asp Arg Thr
325 330 335
Leu Asp Glu Trp Lys Arg Val Thr Tyr Lys Glu Val Leu Ser Phe Lys
340 345 350
Pro Pro Arg Gln Leu Gly Ala Arg Val Ser Lys Glu Thr Pro Leu
355 360 365
<210> 11
<211> 1095
<212> DNA
<213> Homo sapiens
<400> 11
atgagcctca tccggaaaaa gggcttctac aagcaggacg tcaacaagac agcctgggag 60
ctgcccaaga cctacgtgtc cccgacgcac gtcggcagcg gggcctatgg ctccgtgtgc 120
tcggccatcg acaagcggtc aggggagaag gtggccatca agaagctgag ccgacccttt 180
cagtccgaga tcttcgccaa gcgcgcctac cgggagctgc tgctgctgaa gcacatgcag 240
catgagaacg tcattgggct cctggatgtc ttcaccccag cctcctccct gcgcaacttc 300
tatgacttct acctggtgat gcccttcatg cagacggatc tgcagaagat catggggatg 360
gagttcagtg aggagaagat ccagtacctg gtgtatcaga tgctcaaagg ccttaagtac 420
atccactctg ctggggtcgt gcacagggac ctgaagccag gcaacctggc tgtgaatgag 480
gactgtgaac tgaagattct ggattttggg ctggcgcgac atgcagacgc cgagatgact 540
ggctacgtgg tgacccgctg gtaccgagcc cccgaggtga tcctcagctg gatgcactac 600
aaccagacag tggacatctg gtctgtgggc tgtatcatgg cagagatgct gacagggaaa 660
actctgttca aggggaaaga ttacctggac cagctgaccc agatcctgaa agtgaccggg 720
gtgcctggca cggagtttgt gcagaagctg aacgacaaag cggccaaatc ctacatccag 780
tccctgccac agacccccag gaaggatttc actcagctgt tcccacgggc cagcccccag 840
gctgcggacc tgctggagaa gatgctggag ctagacgtgg acaagcgcct gacggccgcg 900
caggccctca cccatccctt ctttgaaccc ttccgggacc ctgaggaaga gacggaggcc 960
cagcagccgt ttgatgattc cttagaacac gagaaactca cagtggatga atggaagcag 1020
cacatctaca aggagattgt gaacttcagc cccattgccc ggaaggactc acggcgccgg 1080
agtggcatga agctg 1095
<210> 12
<211> 1101
<212> DNA
<213> Homo sapiens
<400> 12
atgagctctc cgccgcccgc ccgcagtggc ttttaccgcc aggaggtgac caagacggcc 60
tgggaggtgc gcgccgtgta ccgggacctg cagcccgtgg gctcgggcgc ctacggcgcg 120
gtgtgctcgg ccgtggacgg ccgcaccggc gctaaggtgg ccatcaagaa gctgtatcgg 180
cctttccagt ccgagctgtt cgccaagcgc gcctaccgcg agctgcgcct gctcaagcac 240
atgcgccacg agaacgtgat cgggctgctg gacgtattca ctcctgatga gaccctggat 300
gacttcacgg acttttacct ggtgatgccg ttcatgggca ccgacctggg caagctcatg 360
aaacatgaga agctaggcga ggaccggatc cagttcctcg tgtaccagat gctgaagggg 420
ctgaggtata tccacgctgc cggcatcatc cacagagacc tgaagcccgg caacctggct 480
gtgaacgaag actgtgagct gaagatcctg gacttcggcc tggccaggca ggcagacagt 540
gagatgactg ggtacgtggt gacccggtgg taccgggctc ccgaggtcat cttgaattgg 600
atgcgctaca cgcagacggt ggacatctgg tctgtgggct gcatcatggc ggagatgatc 660
acaggcaaga cgctgttcaa gggcagcgac cacctggacc agctgaagga gatcatgaag 720
gtgacgggga cgcctccggc tgagtttgtg cagcggctgc agagcgatga ggccaagaac 780
tacatgaagg gcctccccga attggagaag aaggattttg cctctatcct gaccaatgca 840
agccctctgg ctgtgaacct cctggagaag atgctggtgc tggacgcgga gcagcgggtg 900
acggcaggcg aggcgctggc ccatccctac ttcgagtccc tgcacgacac ggaagatgag 960
ccccaggtcc agaagtatga tgactccttt gacgacgttg accgcacact ggatgaatgg 1020
aagcgtgtta cttacaaaga ggtgctcagc ttcaagcctc cccggcagct gggggccagg 1080
gtctccaagg agacgcctct g 1101
<210> 13
<211> 30
<212> PRT
<213> Artificial Sequence
<400> 13
Gly Ser Trp Ser His Pro Gln Phe Glu Lys Gly Gly Gly Ser Gly Gly
1 5 10 15
Gly Ser Gly Gly Ser Ala Trp Ser His Pro Gln Phe Glu Lys
20 25 30
<210> 14
<211> 93
<212> DNA
<213> Artificial Sequence
<400> 14
ggatcctgga gccacccgca gttcgagaaa ggtggaggtt ccggaggtgg atcgggaggt 60
tcggcgtgga gccacccgca gttcgaaaaa tga 93
Claims (10)
1.一种特异性结合蛋白激酶p38δ的纳米抗体，其特征在于，所述纳米抗体具有至少一种以下所示的互补决定区：如SEQ ID NO.1所示氨基酸序列的互补决定区CDR1；如SEQ IDNO.2所示氨基酸序列的互补决定区CDR2；和如SEQ ID NO.3所示氨基酸序列的互补决定区CDR3。
2.根据权利要求1所述的特异性结合蛋白激酶p38δ的纳米抗体，其特征在于，所述纳米抗体具有如SEQ ID NO.7所示的氨基酸序列。
3.一种编码权利要求1或2所述的特异性结合蛋白激酶p38δ的纳米抗体的核酸，其特征在于，所述核酸能够编码至少一种以下所示的氨基酸序列：如SEQ ID NO.1所示氨基酸序列；如SEQ ID NO.2所示氨基酸序列；和如SEQ ID NO.3所示氨基酸序列。
4.根据权利要求3所述的核酸，其特征在于，所述核酸具有至少一种以下所示的编码序列：如SEQ ID NO.4所示的编码序列；如SEQ ID NO.5所示的编码序列；和如SEQ ID NO.6所示的编码序列。
5.根据权利要求4所述的核酸，其特征在于，所述核酸具有如SEQ ID NO.8所示的编码序列。
6.一种含有权利要求3至5任一项所述的特异性结合蛋白激酶p38δ的纳米抗体的核酸的表达载体，其特征在于，所述表达载体包括原核生物表达载体、真核生物表达载体或体外表达载体系统。
7.根据权利要求6所述的表达载体，其特征在于，所述表达载体为pET22b。
8.一种含有权利要求6或7所述的表达载体的宿主细胞，其特征在于，所述宿主细胞包括原核生物或真核生物。
9.权利要求1所述的特异性结合蛋白激酶p38δ的纳米抗体在制备用于检测蛋白激酶p38δ的试剂盒中的应用。
10.权利要求1所述的特异性结合蛋白激酶p38δ的纳米抗体在制备治疗或预防与蛋白激酶p38δ调控作用相关的疾病药物中的应用。
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| US6136596A (en) * | 1995-05-19 | 2000-10-24 | University Of Massachusetts | Cytokine-, stress-, and oncoprotein-activated human protein kinase kinases |
| US6140124A (en) * | 1999-04-06 | 2000-10-31 | Isis Pharmaceuticals Inc. | Antisense modulation of P38 mitogen activated protein kinase expression |
| CN1948340A (zh) * | 2005-10-12 | 2007-04-18 | 北京大学 | 与有丝分裂原激活蛋白激酶p38相互作用的蛋白及其编码基因与应用 |
| WO2010047509A2 (ko) * | 2008-10-24 | 2010-04-29 | 아주대학교 산학협력단 | 친화도와 안정성이 향상된 항 ｄｒ5 항체, 및 이를 포함하는 암 예방 또는 치료용 조성물 |
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| US6136596A (en) * | 1995-05-19 | 2000-10-24 | University Of Massachusetts | Cytokine-, stress-, and oncoprotein-activated human protein kinase kinases |
| US6140124A (en) * | 1999-04-06 | 2000-10-31 | Isis Pharmaceuticals Inc. | Antisense modulation of P38 mitogen activated protein kinase expression |
| CN1948340A (zh) * | 2005-10-12 | 2007-04-18 | 北京大学 | 与有丝分裂原激活蛋白激酶p38相互作用的蛋白及其编码基因与应用 |
| WO2010047509A2 (ko) * | 2008-10-24 | 2010-04-29 | 아주대학교 산학협력단 | 친화도와 안정성이 향상된 항 ｄｒ5 항체, 및 이를 포함하는 암 예방 또는 치료용 조성물 |
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