“G-蛋白耦合受体”(GPCRs) 是膜蛋白，充当一系列细胞外信号的传感器，其中包括光子、离子、小有机分子，甚至包括整个蛋白。已知的药物中大约三分之一以GPCRs为作用目标。此前，GPCRs所有已发表的结构都来自A 类GPCRs。在本期Nature 上，两个小组独立报告了B类两个受体的晶体结构。按基本序列和药理，B类是四类GPCRs中的第二大类。Hollenstein等人获得了人“促肾上腺皮质激素释放因子受体-1”的结构。这一GPCR与促肾上腺皮质激素释放激素相结合，后者是内分泌、行为和免疫应激反应的一个强效介质。在所有已知的A类 GPCRs中，配体结合点靠近受体的细胞外边界；在这一GPCR中，拮抗剂 (CP-376395) 在位于V-形受体的胞质部分内的一个疏水腔中结合。Siu等人获得了人“胰高血糖素”受体的X-射线晶体结构。这一GPCR与“胰高血糖素”肽结合，后者触发葡萄糖从肝脏的释放，使其成为2-型糖尿病的一个潜在药物目标。该结构显示了一个比在A 类GPCRs中所见到的更大的配体结合腔。（生物谷Bioon.com）
生物谷推荐英文摘要：
Nature doi: 10.1038/nature12357
Structure of class B GPCR corticotropin-releasing factor receptor 1
Kaspar Hollenstein, James Kean, Andrea Bortolato, Robert K. Y. Cheng, Andrew S. Doré, Ali Jazayeri, Robert M. Cooke, Malcolm Weir & Fiona H. Marshall
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 in complex 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.
Nature doi: 10.1038/nature12393
Structure of the human glucagon class B G-protein-coupled receptor
Fai Yiu Siu, Min He, Chris de Graaf, Gye Won Han, Dehua Yang, Zhiyun Zhang, Caihong Zhou, Qingping Xu, Daniel Wacker, Jeremiah S. Joseph, Wei Liu, Jesper Lau, Vadim Cherezov, Vsevolod Katritch, Ming-Wei Wang & Raymond C. Stevens
Binding of the glucagon peptide to the glucagon receptor (GCGR) triggers the release of glucose from the liver during fasting; thus GCGR plays an important role in glucose homeostasis. Here we report the crystal structure of the seven transmembrane helical domain of human GCGR at 3.4?? resolution, complemented by extensive site-specific mutagenesis, and a hybrid model of glucagon bound to GCGR to understand the molecular recognition of the receptor for its native ligand. Beyond the shared seven transmembrane fold, the GCGR transmembrane domain deviates from class A G-protein-coupled receptors with a large ligand-binding pocket and the first transmembrane helix having a ‘stalk’ region that extends three alpha-helical turns above the plane of the membrane. The stalk positions the extracellular domain (~12?kilodaltons) relative to the membrane to form the glucagon-binding site that captures the peptide and facilitates the insertion of glucagon’s amino terminus into the seven transmembrane domain.
