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Investigation of protein interactions in intrinsic blood coagulation pathway

内在凝血途径中蛋白质相互作用的研究

基本信息

批准号：
7196308
负责人：
DIVI VENKATESWARLU
金额：
$ 21万
依托单位：
NORTH CAROLINA AGRI & TECH ST UNIV
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-02-01 至 2010-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7196308
关键词：
Academic Research Enhancement Awards Address B-domain-deleted factor VIII Binding Biochemical Biochemical Reaction Bioinformatics Biomedical Research Blood Clot Blood coagulation Coagulation Process Complex Computer Simulation Data Databases Defect Disease Disease susceptibility Endopeptidases Engineering Enzyme Precursors Enzymes Event Factor IXa Factor VIIIa Factor X Factor Xa Failure Funding Gene Mutation Goals Hemophilia A Hemophilia B Hemorrhage Historically Black Colleges and Universities Homology Modeling Human Individual Institution Investigation Ions Laboratories Learning Life Medical center Methods Minority Modeling Molecular Molecular Conformation Molecular Structure Multienzyme Complexes Nature Pathway interactions Patients Peptide Hydrolases Phase Phospholipids Play Principal Investigator Production Protein Interaction Mapping Protein-Protein Interaction Map Proteins Proteolysis Rate Reaction Recombinants Reporting Research Research Personnel Research Project Grants Risk Roentgen Rays Role Science Series Serine Protease Site Site-Directed Mutagenesis Solutions Stream Structural Models Structure Structure-Activity Relationship Students Techniques Tertiary Protein Structure Thrombin Thrombosis Training Training Programs Universities aqueous base cancer procoagulant cofactor comparative divalent metal enzyme substrate inhibitor/antagonist interest models and simulation molecular dynamics professor programs protein protein interaction research study therapeutic protein

项目摘要

We propose to employ computational protein modeling and aqueous-phase molecular dynamics methods to develop three-dimensional solution structural models based on partial X-ray crystal structural data and comparative homology modeling techniques. During the requested funding period, we propose to develop structural assembly of multi-domain proteins associated with intrinsic blood coagulation pathway. The specific objectives of the project are: (Aim I): to develop the dynamically equilibrated structural models for factors VIIIa, IXa and FX (Aim II) to model the binary complex between co-factor FVIIIa and factor FIXa (also known as intrinsic Xnase complex). (Aim III) to build the ternary complex among factors FVIIIa, FIXa and zymogen factor FX in an effort to delineate the protein recognition sites during FX activation. (Aim IV) to develop the binary complex between enzyme FIXa and zymogen FX to understand co-factor independent association of FIXa:FX By providing a structural understanding, we hope to address the following questions: i) What specific domains of the individual proteins, i.e., FVIIIa and FIXa, are involved in the intrinsic Xnase complex formation? Ii) How different are the domain-domain interactions and conformations upon co-factor binding? iii) What is the activation mechanism for zymogen FX proteolysis in intrinsic pathway? And iv) Can we decipher the structure-function correlation between the vast amount of hemophilia A and B patient mutational database and the proposed structural models, and if yes, can one use the protein- protein interaction data at the atomic details to engineer the therapeutic proteins? PHS 398/2590 (Rev. 09/04) Page 9 Continuation Format Page Principal Investigator/Program Director (Last, First, Middle): Venkateswarlu, Divi

我们建议采用计算蛋白质建模和水相分子动力学方法开发三维溶液结构模型的基础上部分X-射线晶体结构数据和比较同源建模技术。在申请资助期间，我们建议发展与内在凝血途径相关的多结构域蛋白质的结构组装。该项目的具体目标是：（目标I）：开发因子VIIIa、IXa和FX的动态平衡结构模型（目标II），以模拟辅因子FVIIIa和因子FIXa之间的二元复合物（也称为内在Xnase复合物）。(Aim III）构建因子FVIIIa、FIXa和酶原因子FX之间的三元复合物，以试图描绘FX活化过程中的蛋白质识别位点。(Aim IV）开发酶FIXa和酶原FX之间的二元复合物，以理解FIXa：FX的辅因子独立缔合通过提供结构理解，我们希望解决以下问题：i）单个蛋白质的哪些特定结构域，即，FVIIIa和FIXa参与了内源性Xnase复合物的形成？Ii）在辅因子结合时，结构域-结构域相互作用和构象有多大不同？iii）内源性途径中酶原FX蛋白水解的激活机制是什么？以及iv）我们能否破译大量血友病A和B患者突变数据库与所提出的结构模型之间的结构-功能相关性，如果是的话，我们能否在原子细节上使用蛋白质-蛋白质相互作用数据来设计治疗性蛋白质？PHS 398/2590（2004年9月修订版）第9页续格式页主要研究者/项目负责人（末、首、中）：Venkateswarlu，Divi