Multiple binding sites for the general anesthetic isoflurane identified in the nicotinic acetylcholine receptor transmembrane domain

被引:95
作者
Brannigan, Grace [1 ]
LeBard, David N. [1 ]
Henin, Jerome [2 ]
Eckenhoff, Roderic G. [3 ]
Klein, Michael L. [1 ]
机构
[1] Temple Univ, Inst Computat & Mol Sci, Philadelphia, PA 19122 USA
[2] Aix Marseille Univ, CNRS, Lab Ingn Syst Macromol, F-13402 Marseille, France
[3] Univ Penn, Sch Med, Dept Anesthesiol & Crit Care, Philadelphia, PA 19104 USA
基金
美国国家卫生研究院; 美国国家科学基金会;
关键词
anesthesia; cys-loop receptor; ligand-gated ion channel; GATED ION-CHANNEL; X-RAY-STRUCTURE; MOLECULAR-DYNAMICS; GLYCINE RECEPTORS; GATING MECHANISM; STRUCTURAL BASIS; HIGH-RESOLUTION; GABA(A); PROTEIN; SIMULATIONS;
D O I
10.1073/pnas.1008534107
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
An extensive search for isoflurane binding sites in the nicotinic acetylcholine receptor (nAChR) and the proton gated ion channel from Gloebacter violaceus (GLIC) has been carried out based on molecular dynamics (MD) simulations in fully hydrated lipid membrane environments. Isoflurane introduced into the aqueous phase readily partitions into the lipid membrane and the membrane-bound protein. Specifically, isoflurane binds persistently to three classes of sites in the nAChR transmembrane domain: (i) An isoflurane dimer occludes the pore, contacting residues identified by previous mutagenesis studies; analogous behavior is observed in GLIC. (ii) Several nAChR subunit interfaces are also occupied, in a site suggested by photoaffinity labeling and thought to positively modulate the receptor; these sites are not occupied in GLIC. (iii) Isoflurane binds to the subunit centers of both nAChR a chains and one of the GLIC chains, in a site that has had little experimental targeting. Interpreted in the context of existing structural and physiological data, the present MD results support a multisite model for the mechanism of receptor-channel modulation by anesthetics.
引用
收藏
页码:14122 / 14127
页数:6
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