Conformation of Ligands bound to the muscarinic acetylcholine receptor
Conformation of Ligands bound to the muscarinic acetylcholine receptor
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DOI：
10.1124/mol.62.4.778
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发表时间：
2002-10-01
影响因子：
3.6
通讯作者：
Ishiguro, M
中科院分区：
文献类型：
--
作者：
Furukawa, H;Hamada, T;Ishiguro, M
许多生物胺通过作用于G蛋白偶联受体而引起各种生理反应。我们用核磁共振谱法确定了两种乙酰胆碱类似物(S)甲胆碱和(2S, 4R, 5S)-毒蕈碱与M-2毒蕈碱乙酰胆碱受体（M-2 mAChR）结合的构象。传递核Overhauser效应分析表明，受体选择性识别(S)-甲胆碱和(2S, 4R, 5S)-毒菌碱的O-C2-C1-N二面角为+60度的构象。这与这些配体在没有M-2 mAChR的O-C2-C1-N二面角（+80 - 85度）溶液中的主要构象不同，这是通过耦合常数和核奥弗豪瑟效应光谱分析来评估的。我们还基于视紫红质的x射线晶体结构建立了M-2 mAChR-(S)-甲胆碱复合物的分子模型。该模型表明，O-C2-C1-N二面角为+55.5度的构象，与核磁共振测量结果相似，在能量上有利于(S)-甲胆碱与受体的结合。我们认为这种构象代表了在没有G蛋白的情况下激动剂与M-2 mAChR的结合。
Many biogenic amines evoke a variety of physiological responses by acting on G protein-coupled receptors. We have determined the conformation of two acetylcholine analogs, (S) methacholine and (2S, 4R, 5S)-muscarine, bound to the M-2 muscarinic acetylcholine receptor (M-2 mAChR) by NMR spectroscopy. The analysis of the transferred nuclear Overhauser effect indicated that the receptor selectively recognized the conformers of (S)-methacholine and (2S, 4R, 5S)-muscarine with the gauche O-C2-C1-N dihedral angle at +60degrees. This is distinct from the predominant conformations of these ligands in solution with O-C2-C1-N dihedral angle (+80similar to85degrees) in the absence of the M-2 mAChR, as assessed by analyses of the coupling constants and nuclear Overhauser effect spectroscopy. We have also built a molecular model of the M-2 mAChR-(S)-methacholine complex, based on the X-ray crystallographic structure of rhodopsin. This model indicated that the conformation with the gauche O-C2-C1-N dihedral angle at +55.5degrees, which is similar to the one determined by NMR measurement, is energetically favored in the binding of (S)-methacholine to the receptor. We suggest that this conformation represents the binding of the agonist to the M-2 mAChR in the absence of G protein.