Structural studies interaction between CRF G-protein co

CRF G蛋白co之间的结构研究相互作用

• 批准号: 6956161
• 负责人: ROLAND P RIEK
• 金额: $ 18.97万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6956161
• 关键词: binding sites; corticotropin releasing factor; hormone receptor; neuropeptide receptor; nuclear magnetic resonance spectroscopy; protein structure function; receptor binding; structural biology

Corticotropin releasing factor (CRF) and related ligands play key not only roles in the modulation of adaptive responses of the endocrine, central nervous and immune system to stress but also within the cardiovascular and gastrointestinal systems. The ligand's effects are mediated by binding to CRF G-protein coupled receptors (GPCR's). The aim of this application is the structural elucidation of the interaction between peptides of the CRF family and their receptors. The proposed studies will exploit the specificities of agonist/antagonist-receptor interactions, will elucidate the molecular mechanism of the signaling pathway through the membrane and will facilitate the improvement of drugs targeting stress-related and other diseases. The important observation towards the aims described above is the determination of a major binding site of the CRF family of peptides, which is located in the N-terminal extracellular domain (ECD1) of CRFR's. We determined the three-dimensional NMR structure of the extracellular domain of CRFR2beta and identified its ligand binding site. Here, we propose to elucidate the dynamics and the three-dimensional structures of the extracellular CRF receptors both free and in complex with agonists and antagonists. It is furthermore proposed to determine the three dimensional structure of a hormone analogue when bound to full-length receptor through transferred NOEs and "transferred" residual dipolar couplings, and in parallel, it is aimed to obtain structural insights of the full-length receptor using our established expression protocol of functional CRFR1 in E. coli and TROSY-NMR. We believe that these studies will provide molecular insights of the ligand-receptor specificities and set a structural base for the improvement of drugs targeting stress-related diseases. The structures and dynamics will be determined using standard protocols.

促肾上腺皮质激素释放因子（CRF）及其相关配体不仅在调节内分泌、中枢神经和免疫系统对应激的适应性反应中发挥重要作用，而且在心血管和胃肠道系统中也发挥着重要作用。该配体的作用是通过与CRF - g蛋白偶联受体（GPCR）结合介导的。该应用程序的目的是对CRF家族多肽及其受体之间相互作用的结构阐明。本研究将探索激动剂/拮抗剂-受体相互作用的特异性，阐明通过膜的信号通路的分子机制，并将促进针对应激相关疾病和其他疾病的药物改进。对上述目标的重要观察是确定的一个主要的结合位点