A model of the human M2 muscarinic acetylcholine receptor

被引:30
作者
Jöhren, K [1 ]
Höltje, HD [1 ]
机构
[1] Univ Dusseldorf, Inst Pharmaceut Chem, D-40225 Dusseldorf, Germany
关键词
allosteric binding site; caracurine V derivatives; muscarinic acetylcholine receptor; N-methylscopolamine; orthosteric binding site; protein model; rhodopsin;
D O I
10.1023/A:1023880611709
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The M-2 muscarinic acetylcholine receptor belongs to the family of rhodopsin like G-Protein Coupled Receptors. This subtype of muscarinic receptors is of special interest because it bears, aside from an orthosteric binding site, also an allosteric binding site. Based on the X-ray structure of bovine rhodopsin a complete homology model of the human M-2 receptor was developed. For the orthosteric binding site point mutations and binding studies with different agonists and antagonists are available. This knowledge was utilized for an initial verification of the M-2 model. Allosteric modulation of activity is mediated by structurally different ligands such as gallamine, caracurine V salts or W84 ( a hexamethonium-derivative). Caracurine V derivatives with different affinities to M-2 were docked using GRID- fields. Subsequent molecular dynamics simulations yielded different binding energies based on diverse electrostatic and lipophilic interactions. The calculated affinities are in good agreement to experimentally determined affinities.
引用
收藏
页码:795 / 801
页数:7
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