iHuman Institute, ShanghaiTech University, Shanghai, China.
School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
Adv Exp Med Biol. 2019;1163:225-251. doi: 10.1007/978-981-13-8719-7_10.
G protein-coupled receptors (GPCRs) influence virtually every aspect of human physiology; about one-third of all marketed drugs target members of this family. GPCR allosteric ligands hold the promise of improved subtype selectivity, spatiotemporal sensitivity, and possible biased property over typical orthosteric ligands. However, only a small number of GPCR allosteric ligands have been approved as drugs or in clinical trials since the discovery process is very challenging. The rapid development of GPCR structural biology leads to the discovery of several allosteric sites and sheds light on understanding the mechanism of GPCR allosteric ligands, which is critical for discovering novel therapeutics. This book chapter summarized different GPCR allosteric modulating mechanisms and discussed validated mechanisms based on allosteric modulator-GPCR complex structures.
G 蛋白偶联受体（GPCRs）几乎影响着人类生理学的方方面面；约有三分之一上市的药物针对该家族的成员。GPCR 变构配体有望提高亚型选择性、时空敏感性，并具有相对于典型的正构配体的可能偏向特性。然而，自发现过程极具挑战性以来，仅有少数 GPCR 变构配体被批准为药物或处于临床试验阶段。GPCR 结构生物学的快速发展导致了几个变构结合位点的发现，并阐明了 GPCR 变构配体的作用机制，这对于发现新型治疗药物至关重要。本章总结了不同的 GPCR 变构调节机制，并根据变构调节剂-GPCR 复合物结构讨论了已验证的机制。
