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A Hydrogen Bond in Loop A Is Critical for the Binding and Function of the 5-HT_3 Receptor

Price, Kerry L. and Bower, Kiowa S. and Thompson, Andrew J. and Lester, Henry A. and Dougherty, Dennis A. and Lummis, Sarah C. R. (2008) A Hydrogen Bond in Loop A Is Critical for the Binding and Function of the 5-HT_3 Receptor. Biochemistry, 47 (24). pp. 6370-6377. ISSN 0006-2960. PMCID PMC264937. doi:10.1021/bi800222n.

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The binding sites of Cys-loop receptors are formed from at least six loops (A−F). Here we have used mutagenesis, radioligand binding, voltage clamp electrophysiology, and homology modeling to probe the role of two residues in loop A of the 5-HT_3 receptor: Asn128 and Glu129. The data show that substitution of Asn128, with a range of alternative natural and unnatural amino acids, changed the EC_(50) (from ∼10-fold more potent to ∼10-fold less potent than that of the wild type), increased the maximal peak current for mCPBG compared to 5-HT (R_(max)) 2−19-fold, and decreased n_H, indicating this residue is involved in receptor gating; we propose Asn128 faces away from the binding pocket and plays a role in facilitating transitions between conformational states. Substitutions of Glu129 resulted in functional receptors only when the residue could accept a hydrogen bond, but with both these and other substitutions, no [^3H]granisetron binding could be detected, indicating a role in ligand binding. We propose that Glu129 faces into the binding pocket, where, through its ability to hydrogen bond, it plays a critical role in ligand binding. Thus, the data support a modified model of the 5-HT_3 receptor binding site and show that loop A plays a critical role in both the ligand binding and function of this receptor.

Item Type:Article
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URLURL TypeDescription CentralArticle
Lester, Henry A.0000-0002-5470-5255
Dougherty, Dennis A.0000-0003-1464-2461
Lummis, Sarah C. R.0000-0001-9410-9805
Additional Information:© 2008 American Chemical Society. ACS AuthorChoice. Received 22 November 2007. Published online 22 May 2008. Published in print 1 June 2008. We thank The Wellcome Trust (S.C.R.L. is a Wellcome Trust Senior Research Fellow in Basic Biomedical Science) and the U.S. National Institutes of Health (Grants NS11756 and NS34407) for funding.
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Issue or Number:24
PubMed Central ID:PMC264937
Record Number:CaltechAUTHORS:20170201-090914461
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Official Citation:A Hydrogen Bond in Loop A Is Critical for the Binding and Function of the 5-HT3 Receptor Kerry L. Price, Kiowa S. Bower, Andrew J. Thompson, Henry A. Lester, Dennis A. Dougherty, and Sarah C. R. Lummis Biochemistry 2008 47 (24), 6370-6377 DOI: 10.1021/bi800222n
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:73914
Deposited By: Ruth Sustaita
Deposited On:01 Feb 2017 18:10
Last Modified:11 Nov 2021 05:23

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