iHuman Institute, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai 201210, China.
Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, the Netherlands.
J Mol Biol. 2017 Aug 18;429(17):2726-2745. doi: 10.1016/j.jmb.2017.06.022. Epub 2017 Jul 11.
G protein-coupled receptors (GPCRs) are the largest family of cell surface receptors and are important human drug targets. Of the 826 human GPCRs, 118 of them recognize endogenous peptide or protein ligands, and 30 of the 118 are targeted by approved drug molecules, including the very high-profile class B glucagon-like peptide 1 receptor. In this review, we analyze the 21 experimentally determined three-dimensional structures of the known peptide-binding GPCRs in relation to the endogenous peptides and drug molecules that modulate their cell signaling processes. Our integrated analyses reveal that half of the marketed drugs and most of the drugs in clinical trials that interact with peptide GPCRs are small molecules with a wide range of binding modes distinct from those of large peptide ligands. As we continue to collect additional data on these receptors from orthogonal approaches, including nuclear magnetic resonance and electron microscopy, we are beginning to understand how these receptors interact with their ligands at the molecular level and how improving the pharmacology of GPCR signal transduction requires us to study these receptors using multiple biophysical techniques.
G 蛋白偶联受体（GPCRs）是细胞表面受体中最大的家族，也是重要的人类药物靶点。在 826 个人类 GPCR 中，有 118 个识别内源性肽或蛋白配体，其中 30 个是经批准的药物分子的靶点，包括非常引人注目的 B 类胰高血糖素样肽 1 受体。在这篇综述中，我们分析了已知的肽结合 GPCR 的 21 个实验确定的三维结构，以及调节它们细胞信号转导过程的内源性肽和药物分子。我们的综合分析表明，一半的上市药物和大多数与肽 GPCR 相互作用的临床试验药物都是小分子，其结合模式与大肽配体截然不同。随着我们继续从核磁共振和电子显微镜等正交方法收集这些受体的额外数据，我们开始了解这些受体如何在分子水平上与它们的配体相互作用，以及如何改善 GPCR 信号转导的药理学，需要我们使用多种生物物理技术来研究这些受体。
