G protein-coupled receptors (GPCRs) are the largest family of cell surface receptors, with many GPCRs having crucial roles in endocrinology and metabolism. Cryogenic electron microscopy (cryo-EM) has revolutionized the field of structural biology, particularly regarding GPCRs, over the past decade. Since the first pair of GPCR structures resolved by cryo-EM were published in 2017, the number of GPCR structures resolved by cryo-EM has surpassed the number resolved by X-ray crystallography by 30%, reaching >650, and the number has doubled every ~0.63 years for the past 6 years. At this pace, it is predicted that the structure of 90% of all human GPCRs will be completed within the next 5–7 years. This Review highlights the general structural features and principles that guide GPCR ligand recognition, receptor activation, G protein coupling, arrestin recruitment and regulation by GPCR kinases. The Review also highlights the diversity of GPCR allosteric binding sites and how allosteric ligands could dictate biased signalling that is selective for a G protein pathway or an arrestin pathway. Finally, the authors use the examples of glycoprotein hormone receptors and glucagon-like peptide 1 receptor to illustrate the effect of cryo-EM on understanding GPCR biology in endocrinology and metabolism, as well as on GPCR-related endocrine diseases and drug discovery.

G 蛋白偶联受体 (GPCR) 是最大的细胞表面受体家族，许多 GPCR 在内分泌和代谢中发挥着至关重要的作用。在过去的十年里，低温电子显微镜 (cryo-EM) 彻底改变了结构生物学领域，特别是在 GPCR 方面。自2017年发表第一对冷冻电镜解析的GPCR结构以来，冷冻电镜解析的GPCR结构数量已超过X射线晶体学解析的数量30%，达到>650个，数量翻了一番过去 6 年每约 0.63 年一次。按照这个速度，预计90%的人类GPCR结构将在未来5-7年内完成。本综述重点介绍了指导 GPCR 配体识别、受体激活、G 蛋白偶联、抑制蛋白招募和 GPCR 激酶调节的一般结构特征和原理。该综述还强调了 GPCR 变构结合位点的多样性，以及变构配体如何决定对 G 蛋白途径或抑制蛋白途径具有选择性的偏向信号传导。最后，作者以糖蛋白激素受体和胰高血糖素样肽1受体为例来说明冷冻电镜对于理解内分泌和代谢中的GPCR生物学以及GPCR相关内分泌疾病和药物发现的作用。