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Functional Evaluation of Key Interactions Evident in the Structure of the Eukaryotic Cys-Loop Receptor GluCl

Daeffler, Kristina N.-M. and Lester, Henry A. and Dougherty, Dennis A. (2014) Functional Evaluation of Key Interactions Evident in the Structure of the Eukaryotic Cys-Loop Receptor GluCl. ACS Chemical Biology, 9 (10). pp. 2283-2290. ISSN 1554-8929. PMCID PMC4201344. doi:10.1021/cb500323d.

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The publication of the first high-resolution crystal structure of a eukaryotic Cys-loop receptor, GluClα, has provided valuable structural information on this important class of ligand-gated ion channels (LGIC). However, limited functional data exist for the GluCl receptors. Before applying the structural insights from GluCl to mammalian Cys-loop receptors such as nicotinic acetylcholine and GABA receptors, it is important to ensure that established functional features of mammalian Cys-loop receptors are present in the more distantly related GluCl receptors. Here, we seek to identify ligand-binding interactions that are generally associated with Cys-loop receptors, including the frequently observed cation−π interaction. Our studies were performed on the highly homologous GluClβ receptor, because GluClα is not activated by glutamate in Xenopus laevis oocytes. Mutagenesis of the signal peptide and pore lining helix was performed to enhance functional expression and sensitivity to applied ligand, respectively. Conventional and unnatural amino acid mutagenesis indicate a strong cation−π interaction between Y206 and the protonated amine of glutamate, as well as other important ionic and hydrogen bond interactions between the ligand and the binding site, consistent with the crystal structure.

Item Type:Article
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URLURL TypeDescription Information CentralArticle
Lester, Henry A.0000-0002-5470-5255
Dougherty, Dennis A.0000-0003-1464-2461
Additional Information:© 2014 American Chemical Society. ACS AuthorChoice - This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes. Received: April 29, 2014; accepted: July 22, 2014; Published: July 22, 2014. This work was supported by the National Institutes of Health grant NS034407. We are also grateful for support from the Beckman Institute Zebrafish/Xenopus/Lamprey Facility.
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Caltech Beckman InstituteUNSPECIFIED
Issue or Number:10
PubMed Central ID:PMC4201344
Record Number:CaltechAUTHORS:20140811-132238553
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Official Citation:Functional Evaluation of Key Interactions Evident in the Structure of the Eukaryotic Cys-Loop Receptor GluCl Kristina N.-M. Daeffler, Henry A. Lester, and Dennis A. Dougherty ACS Chemical Biology 2014 9 (10), 2283-2290
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:48319
Deposited By: Jason Perez
Deposited On:11 Aug 2014 21:50
Last Modified:10 Nov 2021 18:31

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