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Multiple Tyrosine Residues Contribute to GABA Binding in the GABA_C Receptor Binding Pocket

Lummis, Sarah C. R. and Harrison, Neil J. and Wang, Jinti and Ashby, Jamie A. and Millen, Katherine S. and Beene, Darren L. and Dougherty, Dennis A. (2012) Multiple Tyrosine Residues Contribute to GABA Binding in the GABA_C Receptor Binding Pocket. ACS Chemical Neuroscience, 3 (3). pp. 186-192. ISSN 1948-7193. PMCID PMC3309607. https://resolver.caltech.edu/CaltechAUTHORS:20120420-144607095

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Abstract

The ligand binding site of Cys-loop receptors is dominated by aromatic amino acids. In GABA_C receptors, these are predominantly tyrosine residues, with a number of other aromatic residues located in or close to the binding pocket. Here we examine the roles of these residues using substitution with both natural and unnatural amino acids followed by functional characterization. Tyr198 (loop B) has previously been shown to form a cation−π interaction with GABA; the current data indicate that none of the other aromatic residues form such an interaction, although the data indicate that both Tyr102 and Phe138 may contribute to stabilization of the positively charged amine of GABA. Tyr247 (loop C) was very sensitive to substitution and, combined with data from a model of the receptor, suggest a π–π interaction with Tyr241 (loop C); here again functional data show aromaticity is important. In addition the hydroxyl group of Tyr241 is important, supporting the presence of a hydrogen bond with Arg104 suggested by the model. At position Tyr102 (loop D) size and aromaticity are important; this residue may play a role in receptor gating and/or ligand binding. The data also suggest that Tyr167, Tyr200, and Tyr208 have a structural role while Tyr106, Trp246, and Tyr251 are not critical. Comparison of the agonist binding site “aromatic box” across the superfamily of Cys-loop receptors reveals some interesting parallels and divergences.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1021/cn200103nDOIArticle
http://pubs.acs.org/doi/abs/10.1021/cn200103nPublisherArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3309607/PubMed CentralArticle
ORCID:
AuthorORCID
Lummis, Sarah C. R.0000-0001-9410-9805
Dougherty, Dennis A.0000-0003-1464-2461
Additional Information:© 2011 American Chemical Society. ACS AuthorChoice. Publication Date (Web): December 15, 2011. Received: October 20, 2011. Revised: December 6, 2011. Funding for this work was received from The Wellcome Trust (S.C.R.L.: WT 81925; S.C.R.L. is a Wellcome Trust Senior Research Fellow in Basic Biomedical Science), the U.S. National Institutes of Health (D.A.D.: NS34407), the Medical Research Council (N.J.H. and K.S.M. held MRC studentships); the European Union (J.A.A.; S.C.R.L.: NeuroCypres FP7). Author Contributions: Participated in research design: S.C.R.L. and D.A.D. Conducted experiments: S.C.R.L., N.J.H., J.W., J.A.A., K.S.M., and D.L.B. Contributed new reagents or analytic tools: D.A.D. Performed data analysis: S.C.R.L., N.J.H., J.W., J.A.A., K.S.M., and D.L.B. Wrote or contributed to the writing of the manuscript: S.C.R.L. and D.A.D.
Funders:
Funding AgencyGrant Number
Wellcome TrustWT 81925
NIHNS34407
Medical Research Council (UK)UNSPECIFIED
European Union (EU) FP7UNSPECIFIED
Subject Keywords:Cys-loop receptor; binding site; unnatural amino acid mutagenesis; cation−π interaction; π−π interaction
Issue or Number:3
PubMed Central ID:PMC3309607
Record Number:CaltechAUTHORS:20120420-144607095
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20120420-144607095
Official Citation:Multiple Tyrosine Residues Contribute to GABA Binding in the GABAC Receptor Binding Pocket Sarah C. R. Lummis, Neil J. Harrison, Jinti Wang, Jamie A. Ashby, Katherine S. Millen, Darren L. Beene, and Dennis A. Dougherty ACS Chemical Neuroscience 2012 3 (3), 186-192
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:30240
Collection:CaltechAUTHORS
Deposited By: Ruth Sustaita
Deposited On:23 Apr 2012 15:56
Last Modified:09 Mar 2020 13:19

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