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From ab initio quantum mechanics to molecular neurobiology: A cation-pi binding site in the nicotinic receptor

Zhong, Wenge and Gallivan, Justin P. and Zhang, Yinong and Li, Lintong and Lester, Henry A. and Dougherty, Dennis A. (1998) From ab initio quantum mechanics to molecular neurobiology: A cation-pi binding site in the nicotinic receptor. Proceedings of the National Academy of Sciences of the United States of America, 95 (21). pp. 12088-12093. ISSN 0027-8424. http://resolver.caltech.edu/CaltechAUTHORS:ZHPpnas98

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Abstract

The nicotinic acetylcholine receptor is the prototype ligand-gated ion channel. A number of aromatic amino acids have been identified as contributing to the agonist binding site, suggesting that cation-pi interactions may be involved in binding the quaternary ammonium group of the agonist, acetylcholine. Here we show a compelling correlation between: (i) ab initio quantum mechanical predictions of cation-pi binding abilities and (ii) EC50 values for acetylcholine at the receptor for a series of tryptophan derivatives that were incorporated into the receptor by using the in vivo nonsense-suppression method for unnatural amino acid incorporation. Such a correlation is seen at one, and only one, of the aromatic residues-tryptophan-149 of the alpha subunit. This finding indicates that, on binding, the cationic, quaternary ammonium group of acetylcholine makes van der Waals contact with the indole side chain of alpha tryptophan-149, providing the most precise structural information to date on this receptor. Consistent with this model, a tethered quaternary ammonium group emanating from position alpha 149 produces a constitutively active receptor.


Item Type:Article
Additional Information:Copyright © 1998 by the National Academy of Sciences. Communicated by John Abelson, California Institute of Technology, Pasadena, CA, August 6, 1998 (received for review June 3, 1998). We thank M. W. Nowak, A. P. West, Jr., C. Labarca, H. Dang, Y. Tong, and Y. Li for helpful discussions. This work was supported by the National Institutes of Health (NS-34407 and NS-11756) and the California Tobacco-Related Disease Research Program. J.P.G. is grateful to the California Institute of Technology and to Eastman Kodak for fellowship support. The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Subject Keywords:nicotinic acetylcholine receptor, cation-pi interaction, unnatural amino acids, acetylcholine-receptor, amino-acids, directed mutagenesis, M2 domain, residues, recognition, resolution, aromatics, mutations, agonists
Record Number:CaltechAUTHORS:ZHPpnas98
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:ZHPpnas98
Alternative URL:http://www.pnas.org/cgi/content/abstract/95/21/12088
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:903
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:07 Nov 2005
Last Modified:26 Dec 2012 08:41

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