Structure of the human M2 muscarinic acetylcholine receptor bound to an antagonist.
Structure of the human M2 muscarinic acetylcholine receptor bound to an antagonist.
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DOI：
10.1038/nature10753
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发表时间：
2012-01-25
期刊：
影响因子：
64.8
通讯作者：
Kobayashi, Takuya
中科院分区：
文献类型：
--
作者：
Haga, Kazuko;Kruse, Andrew C.;Asada, Hidetsugu;Yurugi-Kobayashi, Takami;Shiroishi, Mitsunori;Zhang, Cheng;Weis, William I.;Okada, Tetsuji;Kobilka, Brian K.;Haga, Tatsuya;Kobayashi, Takuya
自主神经系统的副交感神经分支调节多个器官系统的活动。毒蕈碱受体是G蛋白偶联受体（GPCR），其介导对从副交感神经释放的乙酰胆碱的反应。它们在器官和中枢神经系统功能的无意识调节中的作用使它们成为广谱疾病的潜在治疗靶点。M2毒蕈碱乙酰胆碱受体（M2受体）通过激活G蛋白偶联的内向整流钾通道对于心血管功能的生理控制是必需的，并且由于其具有正构和变构配体的广泛药理学特征而特别令人感兴趣。在这里，我们报告的结构拮抗剂结合M2受体，第一个人类乙酰胆碱受体的结构特征。拮抗剂QNB结合在一个长的水性通道的中间，该通道延伸约三分之二通过膜。正构结合口袋由在所有5种毒蕈碱受体亚型中相同的氨基酸形成，并且与来自不同物种的其他功能无关的乙酰胆碱结合蛋白共享结构同源性。酪氨酸残基层形成限制结合配体解离的芳族帽。变构配体的结合位点已被映射到该芳香帽附近的结合口袋入口处的残基。M2受体的结构提供了深入了解的挑战，发展亚型选择性配体的毒蕈碱受体和他们的倾向变构调节。
The parasympathetic limb of the autonomic nervous system regulates the activity of multiple organ systems. Muscarinic receptors are G protein coupled receptors (GPCRs) that mediate the response to acetylcholine released from parasympathetic nerves. Their role in the unconscious regulation of organ and central nervous system function makes them potential therapeutic targets for a broad spectrum of diseases. The M2 muscarinic acetylcholine receptor (M2 receptor) is essential for the physiologic control of cardiovascular function through activation of G protein-coupled inwardly-rectifying potassium channels, and is of particular interest because of its extensive pharmacological characterization with both orthosteric and allosteric ligands. Here we report the structure of antagonist-bound M2 receptor, the first human acetylcholine receptor to be characterized structurally. The antagonist QNB binds in the middle of a long aqueous channel extending approximately two-thirds through the membrane. The orthosteric binding pocket is formed by amino acids that are identical in all 5 muscarinic receptor subtypes, and shares structural homology with other functionally unrelated acetylcholine binding proteins from different species. A layer of tyrosine residues forms an aromatic cap restricting dissociation of the bound ligand. A binding site for allosteric ligands has been mapped to residues at the entrance to the binding pocket near this aromatic cap. The M2 receptor structure provides insights into the challenges of developing subtype-selective ligands for muscarinic receptors and their propensity for allosteric regulation.
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影响因子：
6.4
作者：
Asada H;Uemura T;Yurugi-Kobayashi T;Shiroishi M;Shimamura T;Tsujimoto H;Ito K;Sugawara T;Nakane T;Nomura N;Murata T;Haga T;Iwata S;Kobayashi T
通讯作者：
Kobayashi T
影响因子：
3.6
作者：
Furukawa, H;Hamada, T;Ishiguro, M
通讯作者：
Ishiguro, M
DOI：
10.1111/j.1432-1033.1994.tb20050.x
发表时间：
1994-12-01
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
KAMEYAMA, K;HAGA, K;SADEE, W
通讯作者：
SADEE, W
影响因子：
14.8
作者：
通讯作者：
--
强大的体积溶剂校正和各向异性缩放程序。
DOI：
10.1107/s0907444905007894
发表时间：
2005-07
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Afonine PV;Grosse-Kunstleve RW;Adams PD
通讯作者：
Adams PD