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Chemical Scale Studies of the Phe-Pro Conserved Motif in the Cys Loop of Cys

Limapichat, Walrati and Lester, Henry A. and Dougherty, Dennis A. (2010) Chemical Scale Studies of the Phe-Pro Conserved Motif in the Cys Loop of Cys. Journal of Biological Chemistry, 285 (12). pp. 8976-8984. ISSN 0021-9258. PMCID PMC2838319. doi:10.1074/jbc.M109.060939.

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The functions of two conserved residues, Phe^(135) and Pro^(136), located at the apex of the Cys loop of the nicotinic acetylcholine receptor are investigated. Both residues were substituted with natural and unnatural amino acids, focusing on the role of aromaticity at Phe^(135), backbone conformation at Pro^(136), side chain polarity and volume, and the specific interaction between the aromatic side chain and the proline. NMR spectroscopy studies of model peptides containing proline and unnatural proline analogues following a Phe show a consistent increase in the population of the cis conformer relative to peptides lacking the Phe. In the receptor, a strong interaction between the Phe and Pro residues is evident, as is a strong preference for aromaticity and hydrophobicity at the Phe site. A similar influence of hydrophobicity is observed at the proline site. In addition, across a simple homologous series of proline analogues, the results reveal a correlation between receptor function and cis bias at the proline backbone. This could suggest a significant role for the cis proline conformer at this site in receptor function.

Item Type:Article
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URLURL TypeDescription CentralArticle
Lester, Henry A.0000-0002-5470-5255
Dougherty, Dennis A.0000-0003-1464-2461
Additional Information:© 2010 American Society for Biochemistry and Molecular Biology. Received August 28, 2009; revision received January 8, 2010. This work was supported, in whole or in part, by National Institutes of Health Grants NS-34407 and NS-11756. We thank Dr. Scott A. Ross for help with the NMR experiments and Professor Sarah C. R. Lummis for helpful discussion.
Funding AgencyGrant Number
Subject Keywords:Peptides/Conformation; Receptors/7-Helix Ligand-gated Channels; Receptors/Structure-Function; Ion Channels; Nicotinic Acetylcholine Receptors; Cys Loop; Nicotinic Receptor; Proline; Unnatural Amino Acid Mutagenesis
Issue or Number:12
PubMed Central ID:PMC2838319
Record Number:CaltechAUTHORS:20100409-120603576
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Official Citation:Walrati Limapichat, Henry A. Lester, and Dennis A. Dougherty Chemical Scale Studies of the Phe-Pro Conserved Motif in the Cys Loop of Cys Loop Receptors J. Biol. Chem. 2010 285: 8976-8984. First Published on January 12, 2010, doi:10.1074/jbc.M109.060939
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:17916
Deposited By: Jason Perez
Deposited On:14 May 2010 18:13
Last Modified:08 Nov 2021 23:39

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