A Stereochemical Test of a Proposed Structural Feature of the Nicotinic Acetylcholine Receptor
Abstract
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.
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 http://pubs.acs.org.Attached Files
Supplemental Material - ja8015457-File002.pdf
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Additional details
- Eprint ID
- 12139
- DOI
- 10.1021/ja8015457
- Resolver ID
- CaltechAUTHORS:HANjacs08
- NIH
- NS 34407
- NIH
- NS 11756
- NIH Predoctoral Fellowship
- 5T32GM07616
- Created
-
2008-10-24Created from EPrint's datestamp field
- Updated
-
2021-11-08Created from EPrint's last_modified field