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A Stereochemical Test of a Proposed Structural Feature of the Nicotinic Acetylcholine Receptor

Hanek, Ariele P. and Lester, Henry A. and Dougherty, Dennis A. (2008) A Stereochemical Test of a Proposed Structural Feature of the Nicotinic Acetylcholine Receptor. Journal of the American Chemical Society, 130 (40). pp. 13216-13218. ISSN 0002-7863.

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Understanding the gating mechanism of the nicotinic acetylcholine receptor (nAChR) and similar channels constitutes a significant challenge in chemical neurobiology. In the present work, we use a stereochemical probe to evaluate a proposed pin-into-hydrophobic socket mechanism for the αVal46 side chain of the nAChR. Utilizing nonsense suppression methodology we incorporated isoleucine (Ile), O-methyl threonine (Omt) and threonine (Thr) as well as their side chain epimers (the allo counterparts). Surprisingly, our results indicate that only the pro-S methyl group of the αVal46 side chain is sensitive to changes in hydrophobicity, consistent with the precise geometrical requirements of the pin-into-socket mechanism.

Item Type:Article
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URLURL TypeDescription
Lester, Henry A.0000-0002-5470-5255
Dougherty, Dennis A.0000-0003-1464-2461
Additional Information:© 2008 American Chemical Society. Received March 6, 2008. Web Release Date: September 10, 2008. We thank the National Institutes of Health for their generous support (grants NS 34407 and NS 11756 and predoctoral training grant 5T32GM07616). Supporting Information Available: Experimental procedures for incorporation of unnatural amino acids and electrophysiological evaluation of mutants, dose response curves for mutations discussed herein, sample traces of select mutants, discussion of previously reported conventional mutants, as well as the synthesis and characterization of NVOC-aThr cyano-methyl ester. This material is available free of charge via the Internet at
Funding AgencyGrant Number
NIHNS 34407
NIHNS 11756
NIH Predoctoral Fellowship5T32GM07616
Issue or Number:40
Record Number:CaltechAUTHORS:HANjacs08
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:12139
Deposited By: Archive Administrator
Deposited On:24 Oct 2008 23:04
Last Modified:03 Oct 2019 00:25

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