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GABA Binding to an Insect GABA Receptor: A Molecular Dynamics and Mutagenesis Study

Ashby, Jamie A. and McGonigle, Ian V. and Price, Kerry L. and Cohen, Netta and Comitani, Federico and Dougherty, Dennis A. and Molteni, Carla and Lummis, Sarah C. R. (2012) GABA Binding to an Insect GABA Receptor: A Molecular Dynamics and Mutagenesis Study. Biophysical Journal, 103 (10). pp. 2071-2081. ISSN 0006-3495. PMCID PMC3512037. doi:10.1016/j.bpj.2012.10.016.

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RDL receptors are GABA-activated inhibitory Cys-loop receptors found throughout the insect CNS. They are a key target for insecticides. Here, we characterize the GABA binding site in RDL receptors using computational and electrophysiological techniques. A homology model of the extracellular domain of RDL was generated and GABA docked into the binding site. Molecular dynamics simulations predicted critical GABA binding interactions with aromatic residues F206, Y254, and Y109 and hydrophilic residues E204, S176, R111, R166, S176, and T251. These residues were mutated, expressed in Xenopus oocytes, and their functions assessed using electrophysiology. The data support the binding mechanism provided by the simulations, which predict that GABA forms many interactions with binding site residues, the most significant of which are cation-π interactions with F206 and Y254, H-bonds with E204, S205, R111, S176, T251, and ionic interactions with R111 and E204. These findings clarify the roles of a range of residues in binding GABA in the RDL receptor, and also show that molecular dynamics simulations are a useful tool to identify specific interactions in Cys-loop receptors.

Item Type:Article
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URLURL TypeDescription CentralArticle
Dougherty, Dennis A.0000-0003-1464-2461
Lummis, Sarah C. R.0000-0001-9410-9805
Additional Information:© 2012 by the Biophysical Society. This is an Open Access article distributed under the terms of the Creative Commons-Attribution Noncommercial License (, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Submitted March 30, 2012, and accepted for publication October 11, 2012. We acknowledge financial support from TheWellcome Trust (WT 81925 to SCRL; SCRL is a Wellcome Trust Senior Research Fellow in Basic Biomedical Science), the European Union 7th Framework Program No. HEALTH-F2-2007-202088 ("NeuroCypres" project) to SCRL; the Medical Research Council (a studentship to I.McG.), the U. S. National Institutes of Health (NS34407 to D.A.D.), and the EPSRC (EP/F037457/1 "Support for the UK Car-Parrinello Consortium") to CM.
Funding AgencyGrant Number
Wellcome TrustWT 81925
European Union 7th Framework ProgramHEALTH-F2-2007-202088
Medical Research Council (UK)UNSPECIFIED
Engineering and Physical Sciences Research Council (EPSRC)EP/F037457/1
Issue or Number:10
PubMed Central ID:PMC3512037
Record Number:CaltechAUTHORS:20130104-082120331
Persistent URL:
Official Citation:Jamie A. Ashby, Ian V. McGonigle, Kerry L. Price, Netta Cohen, Federico Comitani, Dennis A. Dougherty, Carla Molteni, Sarah C.R. Lummis, GABA Binding to an Insect GABA Receptor: A Molecular Dynamics and Mutagenesis Study, Biophysical Journal, Volume 103, Issue 10, 21 November 2012, Pages 2071-2081, ISSN 0006-3495, 10.1016/j.bpj.2012.10.016. (
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:36161
Deposited By: Ruth Sustaita
Deposited On:04 Jan 2013 16:45
Last Modified:09 Nov 2021 23:20

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