MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom; email:
Current affiliation: Institute for Biocomputation and Physics of Complex Systems (BIFI) and Laboratorio de Microscopias Avanzadas, University of Zaragoza, 50018 Zaragoza, Spain; email:
Annu Rev Pharmacol Toxicol. 2020 Jan 6;60:51-71. doi: 10.1146/annurev-pharmtox-010919-023545. Epub 2019 Jul 26.
Electron cryo-microscopy (cryo-EM) has revolutionized structure determination of membrane proteins and holds great potential for structure-based drug discovery. Here we discuss the potential of cryo-EM in the rational design of therapeutics for membrane proteins compared to X-ray crystallography. We also detail recent progress in the field of drug receptors, focusing on cryo-EM of two protein families with established therapeutic value, the γ-aminobutyric acid A receptors (GABARs) and G protein-coupled receptors (GPCRs). GABARs are pentameric ion channels, and cryo-EM structures of physiological heteromeric receptors in a lipid environment have uncovered the molecular basis of receptor modulation by drugs such as diazepam. The structures of ten GPCR-G protein complexes from three different classes of GPCRs have now been determined by cryo-EM. These structures give detailed insights into molecular interactions with drugs, GPCR-G protein selectivity, how accessory membrane proteins alter receptor-ligand pharmacology, and the mechanism by which HIV uses GPCRs to enter host cells.
电子冷冻显微镜（cryo-EM）彻底改变了膜蛋白的结构测定，并且在基于结构的药物发现方面具有很大的潜力。在这里，我们将讨论与 X 射线晶体学相比，cryo-EM 在膜蛋白治疗药物的合理设计中的潜力。我们还详细介绍了药物受体领域的最新进展，重点介绍了具有既定治疗价值的两类蛋白质家族的 cryo-EM，γ-氨基丁酸 A 受体（GABARs）和 G 蛋白偶联受体（GPCRs）。GABARs 是五聚体离子通道，在脂质环境中具有生理异源受体的 cryo-EM 结构揭示了药物如地西泮对受体调节的分子基础。现在已经通过 cryo-EM 确定了来自三种不同 GPCR 类别的十个 GPCR-G 蛋白复合物的结构。这些结构深入了解了与药物的分子相互作用、GPCR-G 蛋白选择性、辅助膜蛋白如何改变受体配体药理学以及 HIV 如何利用 GPCR 进入宿主细胞的机制。
