Structure of class B GPCR corticotropin-releasing factor receptor 1
Structure of class B GPCR corticotropin-releasing factor receptor 1
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DOI：
10.1038/nature12357
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发表时间：
2013-07-25
期刊：
影响因子：
64.8
通讯作者：
Marshall, Fiona H.
中科院分区：
文献类型：
--
作者：
Hollenstein, Kaspar;Kean, James;Marshall, Fiona H.
B类G蛋白偶联受体（GPCR），对肽类激素有反应的细胞表面蛋白，其结构分析仅限于氨基末端胞外结构域，因此对跨膜信号转导结构域的了解很少。促肾上腺皮质激素释放因子受体1型是介导应激反应的B类受体，并且被认为是抑郁症和焦虑症的药物靶点。在这里，我们报告的晶体结构的跨膜结构域的人促肾上腺皮质激素释放因子受体1型incomplex与小分子拮抗剂CP-376395。该结构提供了对B类受体结构的详细了解。描述了受体与结合在受体深处的非肽配体的相互作用的原子细节。这种结构为所有B类GPCR提供了模型，并可能有助于设计用于脑部和代谢疾病的新型小分子药物。
Structural analysis of class B G-protein-coupled receptors (GPCRs), cell-surface proteins that respond to peptide hormones, has been restricted to the amino-terminal extracellular domain, thus providing little understanding of the membrane-spanning signal transduction domain. The corticotropin-releasing factor receptor type 1 is a class B receptor which mediates the response to stress and has been considered a drug target for depression and anxiety. Here we report the crystal structure of the transmembrane domain of the human corticotropin-releasing factor receptor type 1 incomplex with the small-molecule antagonist CP-376395. The structure provides detailed insight into the architecture of class B receptors. Atomic details of the interactions of the receptor with the non-peptide ligand that binds deep within the receptor are described. This structure provides a model for all class B GPCRs and may aid in the design of new small-molecule drugs for diseases of brain and metabolism.