Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville 3052, Victoria Australia; ARC Centre for Cryo-electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville 3052, Victoria Australia.
Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville 3052, Victoria Australia; ARC Centre for Cryo-electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville 3052, Victoria Australia. Electronic address: https://twitter.com/@JesseMobbs.
Curr Opin Struct Biol. 2023 Apr;79:102560. doi: 10.1016/j.sbi.2023.102560. Epub 2023 Feb 26.
G-protein coupled receptors (GPCRs) are important therapeutic targets for the treatment of human disease. Although GPCRs are highly successful drug targets, there are many challenges associated with the discovery and translation of small molecule ligands that target the endogenous ligand-binding site for GPCRs. Allosteric modulators are a class of ligands that target alternative binding sites known as allosteric sites and offer fresh opportunities for the development of new therapeutics. However, only a few allosteric modulators have been approved as drugs. Advances in GPCR structural biology enabled by the cryogenic electron microscopy (cryo-EM) revolution have provided new insights into the molecular mechanism and binding location of small molecule allosteric modulators. This review highlights the latest findings from allosteric modulator-bound structures of Class A, B, and C GPCRs with a focus on small molecule ligands. Emerging methods that will facilitate cryo-EM structures of more difficult ligand-bound GPCR complexes are also discussed. The results of these studies are anticipated to aid future structure-based drug discovery efforts across many different GPCRs.
G 蛋白偶联受体（GPCRs）是治疗人类疾病的重要治疗靶点。尽管 GPCR 是非常成功的药物靶点，但在发现和翻译靶向 GPCR 内源性配体结合位点的小分子配体方面仍存在许多挑战。变构调节剂是一类靶向称为变构位点的替代结合位点的配体，为开发新的治疗方法提供了新的机会。然而，只有少数变构调节剂被批准为药物。低温电子显微镜（cryo-EM）革命推动的 GPCR 结构生物学的进步，为小分子变构调节剂的分子机制和结合位置提供了新的见解。本综述重点介绍了配体结合结构的最新发现，包括 A、B 和 C 类 GPCR，重点介绍了小分子配体。还讨论了将促进更困难的配体结合 GPCR 复合物的 cryo-EM 结构的新兴方法。预计这些研究结果将有助于未来在许多不同的 GPCR 中进行基于结构的药物发现工作。
