Toward a Structural Understanding of Class B GPCR Peptide Binding and Activation
Toward a Structural Understanding of Class B GPCR Peptide Binding and Activation
复制标题
DOI：
10.1016/j.molcel.2020.01.012
复制
发表时间：
2020-02-06
期刊：
影响因子：
16
通讯作者：
Wootten, Denise
中科院分区：
文献类型：
--
作者：
Liang, Yi-Lynn;Belousoff, Matthew J.;Wootten, Denise
B类G蛋白偶联受体（GPCR）是重大疾病的重要治疗靶点。在这里，我们提出的肽和Gsbound垂体腺苷酸环化酶激活肽，PAC 1受体和促肾上腺皮质激素释放因子（CRF），（CRF 1）受体的结构。连同最近解决的结构，这些提供了主要的B类气相化学还原酶亚族的覆盖面。在不同的受体中，细胞外结构域到受体核心的不同取向至少部分取决于肽相互作用的结构和性质的进化保守性。与受体核心的肽相互作用的差异也影响相互连接的TM 2-TM 1-TM 6/ECL 3/TM 7结构域，这可能在其不同的信号传导中很重要。然而，与ICL 2重组相关的ECL 2常见构象重组调节G蛋白接触。受体之间的比较揭示了ICL 2作为以受体和配体特异性方式形成动态G蛋白相互作用的关键结构域。这项工作推进了我们对B类GPCR激活和Gs偶联的理解。
Class B G protein-coupled receptors (GPCRs) are important therapeutic targets for major diseases. Here, we present structures of peptide and Gsbound pituitary adenylate cyclase-activating peptide, PAC1 receptor, and corticotropin-releasing factor (CRF), (CRF1) receptor. Together with recently solved structures, these provide coverage of the major class B GPCR subfamilies. Diverse orientations of the extracellular domain to the receptor core in different receptors are at least partially dependent on evolutionary conservation in the structure and nature of peptide interactions. Differences in peptide interactions to the receptor core also influence the interlinked TM2-TM1-TM6/ECL3/TM7 domain, and this is likely important in their diverse signaling. However, common conformational reorganization of ECL2, linked to reorganization of ICL2, modulates G protein contacts. Comparison between receptors reveals ICL2 as a key domain forming dynamic G protein interactions in a receptor- and ligand-specific manner. This work advances our understanding of class B GPCR activation and Gs coupling.