UNDERSTANDING THE ARCHITECTURE OF CHALLENGING MULTI-DOMAIN PROTEINS

了解具有挑战性的多域蛋白质的结构

• 批准号: 8362303
• 负责人: ANDREW M GULICK
• 金额: $ 0.19万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8362303
• 关键词: Amino Acids; Architecture; Binding; Biochemical; Biological Assay; Biological Factors; Catalytic Domain; Cells; Crystallography; Development; Enzymes; Funding; GRP94; Grant; Heat-Shock Proteins 90; Investigation; Ligands; Molecular Chaperones; National Center for Research Resources; Peptide Antibiotics; Peptides; Principal Investigator; Proteins; Radiation; Research; Research Infrastructure; Resources; Siderophores; Source; Specificity; Tertiary Protein Structure; United States National Institutes of Health; base; cost; novel; peptide synthase; protein function; small molecule; structural biology

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. This is a proposal describing research into multi-domain and multi-protein assemblies under study in our labs. The Gulick lab is investigating the structural arrangement of non-ribosomal peptide synthetases (NRPSs). These modular proteins catalyze the synthesis of peptides antibiotics and peptide siderophores using amino acid and peptide intermediates that are covalently bound to a carrier domain that delivers substrates to the necessary catalytic domains in a coordinated fashion. The choreography of this assembly line synthesis is being investigated through biochemical studies and structural investigations of multi-domain proteins trapped in catalytically relevant states. Additional projects investigate auxiliary proteins that function with NRPS enzymes in the synthesis of natural products. The Gewirth lab studies the multi-domain HSP90 class of molecular chaperones. Questions at the forefront of the field currently center on the development of inhibitory ligands of high specificity, as well as understanding the mechanistic differences between cytoplasmic Hsp90 and GRP94. We are using x-ray crystallography in combination with biochemical and cell-based assays to study the interaction of the hsp90 family of molecular chaperones with novel small molecule inhibitory ligands.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 这是一项描述我们实验室正在研究的多域和多蛋白质组装研究的提案。 Gulick 实验室正在研究非核糖体肽合成酶 (NRPS) 的结构排列。这些模块蛋白使用共价结合到载体结构域的氨基酸和肽中间体催化肽抗生素和肽铁载体的合成，载体结构域以协调的方式将底物递送到必要的催化结构域。正在通过生物化学研究和陷入催化相关状态的多结构域蛋白质的结构研究来研究这种装配线合成的编排。其他项目研究在天然产物合成中与 NRPS 酶一起发挥作用的辅助蛋白。 Gewirth 实验室研究多结构域 HSP90 类分子伴侣。目前该领域最前沿的问题集中在高特异性抑制性配体的开发，以及了解细胞质 Hsp90 和 GRP94 之间的机制差异。我们使用 X 射线晶体学结合生化和细胞测定来研究 hsp90 分子伴侣家族与新型小分子抑制配体的相互作用。