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

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 ch...

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Bibliographic Details
Published in:Journal of the American Chemical Society 2008-10, Vol.130 (40), p.13216-13218
Main Authors: Hanek, Ariele P, Lester, Henry A, Dougherty, Dennis A
Format: Article
Language:English
Subjects:
Models, Molecular
Mutation - genetics
Protein Structure, Quaternary
Protein Subunits - chemistry
Receptors, Nicotinic - chemistry
Receptors, Nicotinic - genetics
Receptors, Nicotinic - metabolism
Stereoisomerism
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Summary: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.
ISSN:0002-7863
1520-5126
DOI:10.1021/ja8015457