Crystal structures of the M1 and M4 muscarinic acetylcholine receptors.
Crystal structures of the M1 and M4 muscarinic acetylcholine receptors.
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DOI：
10.1038/nature17188
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发表时间：
2016-03-17
期刊：
影响因子：
64.8
通讯作者：
Christopoulos A
中科院分区：
文献类型：
--
作者：
Thal DM;Sun B;Feng D;Nawaratne V;Leach K;Felder CC;Bures MG;Evans DA;Weis WI;Bachhawat P;Kobilka TS;Sexton PM;Kobilka BK;Christopoulos A
毒蕈碱M1-M5乙酰胆碱受体是G蛋白偶联受体（GPCR），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系统疾病（如阿尔茨海默病和精神分裂症）的有吸引力的药物靶标，但乙酰胆碱结合口袋的高度保守性促使目前的研究靶向这些受体上的变构位点。在这里，我们报告的第一个晶体结构的M1和M4毒蕈碱受体结合的反向激动剂，噻托溴铵。这些结构相互比较，以及先前报道的M2和M3受体结构，揭示了在正构和变构结合位点的差异，这有助于在这个重要的受体家族的药物选择性的作用。我们还报告了一组残基的鉴定，这些残基形成了连接M4受体的正构和变构位点的网络，这为变构调制如何在两个空间上不同的结构域之间传输提供了新的见解。
Muscarinic M1–M5 acetylcholine receptors are G protein-coupled receptors (GPCRs) 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 first crystal structures of the M1 and M4 muscarinic receptors bound to the inverse agonist, tiotropium. Comparison of these structures to each other, as well as 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.