Thal David M, Sun Bingfa, Feng Dan, Nawaratne Vindhya, Leach Katie, Felder Christian C, Bures Mark G, Evans David A, Weis William I, Bachhawat Priti, Kobilka Tong Sun, Sexton Patrick M, Kobilka Brian K, Christopoulos Arthur
Drug Discovery Biology and Department of Pharmacology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, 3052, Victoria, Australia.
ConfometRx, 3070 Kenneth Street, Santa Clara, California 95054, USA.
Nature. 2016 Mar 17;531(7594):335-40. doi: 10.1038/nature17188. Epub 2016 Mar 9.
Muscarinic M1-M5 acetylcholine receptors are G-protein-coupled receptors that regulate many vital functions of the central and peripheral nervous systems. In particular, the M1 and M4 receptor subtypes have emerged as attractive drug targets for treatments of neurological disorders, such as Alzheimer's disease and schizophrenia, but the high conservation of the acetylcholine-binding pocket has spurred current research into targeting allosteric sites on these receptors. Here we report the crystal structures of the M1 and M4 muscarinic receptors bound to the inverse agonist, tiotropium. Comparison of these structures with each other, as well as with the previously reported M2 and M3 receptor structures, reveals differences in the orthosteric and allosteric binding sites that contribute to a role in drug selectivity at this important receptor family. We also report identification of a cluster of residues that form a network linking the orthosteric and allosteric sites of the M4 receptor, which provides new insight into how allosteric modulation may be transmitted between the two spatially distinct domains.
毒蕈碱型M1 - M5乙酰胆碱受体是G蛋白偶联受体，可调节中枢和外周神经系统的许多重要功能。特别是，M1和M4受体亚型已成为治疗神经疾病（如阿尔茨海默病和精神分裂症）的有吸引力的药物靶点，但乙酰胆碱结合口袋的高度保守性促使目前对这些受体变构位点的靶向研究。在此，我们报道了与反向激动剂噻托溴铵结合的M1和M4毒蕈碱受体的晶体结构。将这些结构相互比较，以及与先前报道的M2和M3受体结构进行比较，揭示了正构和变构结合位点的差异，这些差异有助于在这个重要的受体家族中发挥药物选择性作用。我们还报道了鉴定出一组形成连接M4受体正构和变构位点网络的残基，这为变构调节如何在两个空间上不同的结构域之间传递提供了新的见解。
