STRUCTURAL STUDIES OF SIGNALING MOLECULES FROM M TUBERCULOSIS

结核分枝杆菌信号分子的结构研究

• 批准号: 7598233
• 负责人: Laurie M Gay
• 金额: $ 0.02万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-01 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7598233
• 关键词: Allosteric Regulation; Binding; Computer Retrieval of Information on Scientific Projects Database; Dimerization; Extracellular Domain; Funding; Grant; Homodimerization; Institution; Ligand Binding; Membrane; Modeling; Mycobacterium tuberculosis; Nucleotides; Phosphotransferases; Protein Analysis; Protein-Serine-Threonine Kinases; Proteins; Range; Regulation; Regulatory Pathway; Research; Research Personnel; Resources; Sequence Homology; Signaling Molecule; Source; Structure; Time; Tuberculosis; United States National Institutes of Health; design; inhibitor/antagonist; pathogenic bacteria; sensor; serine receptor

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Membrane bound serine/threonine protein kinases (STPKs) are essential components of regulatory pathways in the pathogenic bacterium Mycobacterium tuberculosis, the causative agent of tuberculosis. Nine single-pass, transmembrane kinases are present in TB and these paralogous proteins share significant sequence homology (30-60%), indicating conservation of structure and mechanism. Structural analysis of these proteins is discovering important facts related to global regulation of kinase activity and possible mechanisms for the design of discriminating inhibitors. Our previous crystallographic models of kinase domains of PknE and PknB have implicated homodimerization as a mechanism for allosteric regulation of kinase activity. Structural studies of the enzymatic domains have provided clues towards the mechanism of dimerization, but models comprising a range of ligand-bound and catalytic states are necessary for complete understanding of dimerization and the catalytic cycle. Furthermore, the structure of the extracellular domain of PknE is required to demonstrate the function of this domain in dimerization and kinase regulation. I have crystallized the PknE kinase domain with bound nucleotide and the PknE sensor domain. I request beam time at SSRL to determine these structures which have the potential to reveal for the first time both the intracellular and extracellular domains of a bacterial receptor STPK.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 膜结合丝氨酸/苏氨酸蛋白激酶 (STPK) 是结核病致病菌结核分枝杆菌调节途径的重要组成部分。 结核病中存在九种单次跨膜激酶，这些旁系同源蛋白具有显着的序列同源性 (30-60%)，表明结构和机制的保守性。 这些蛋白质的结构分析发现了与激酶活性整体调节相关的重要事实以及设计区分抑制剂的可能机制。 我们之前的 PknE 和 PknB 激酶结构域晶体学模型表明同二聚化是激酶活性变构调节的机制。 酶结构域的结构研究为二聚化机制提供了线索，但包含一系列配体结合和催化状态的模型对于完全理解二聚化和催化循环是必要的。 此外，需要 PknE 胞外结构域的结构来证明该结构域在二聚化和激酶调节中的功能。 我已经结晶了带有结合核苷酸的 PknE 激酶结构域和 PknE 传感器结构域。 我请求 SSRL 进行光束时间来确定这些结构，这些结构有可能首次揭示细菌受体 STPK 的细胞内和细胞外结构域。