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Prediction of the 3-D structure of rat MrgA G protein-coupled receptor and identification of its binding site

Heo, Jiyoung and Vaidehi, Nagarajan and Wendel, John and Goddard, William A., III (2007) Prediction of the 3-D structure of rat MrgA G protein-coupled receptor and identification of its binding site. Journal of Molecular Graphics and Modelling, 26 (4). pp. 800-812. ISSN 1093-3263. PMCID PMC2151207.

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Mrg receptors are orphan G protein-coupled receptors (GPCRs) located mainly at the specific set of sensory neurons in the dorsal root ganglia, suggesting a role in nociception. We report here the 3-D structure of rat MrgA (rMrgA) receptor [obtained from homology modeling to the recently validated predicted structures of mouse MrgA1 and MrgC11] and the structure of adenine (a known agonist, Ki = 18 nM) bound to rMrgA. This predicted binding site is located within transmembrane helical domains (TMs) 3, 4, 5 and 6, with Asn residues in TM3 and TM4 identified as the key residues for adenine binding. Here the side chain of Asn88 (TM3) forms two pairs of hydrogen bonds with N3 and N9 of adenine while Asn146 (TM4) makes two pairs of hydrogen bonds with N1 and N6 of adenine. These interactions lock adenine tightly in the binding pocket. We also predict the binding site of guanine (not an agonist) and seven other derivatives. Guanine cannot make the hydrogen bond to Asn146 (TM4), leading to binding too weak to be observed experimentally. The predicted binding affinity for other adenine derivatives correlates with the availability of the hydrogen bonds to these two Asn residues. These results validate the predicted structure for rat MrgA and suggest mutation experiments that could further validate the structure. Moreover, the predicted structure and binding site should be useful for seeking other small molecule agonists and antagonists.

Item Type:Article
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URLURL TypeDescription CentralArticle
Goddard, William A., III0000-0003-0097-5716
Additional Information:© 2007 Elsevier Inc. Received 31 May 2007, Revised 9 July 2007, Accepted 11 July 2007, Available online 16 July 2007. We thank Prof. Mel Simon for suggesting this project. This research was supported partially by NIH (MH073910, CA112293, AI040567), and the computational facilities were provided by DURIP grants from ARO and ONR. The facilities of the Materials and Process Simulation Center are also supported by DOE (ASC), NSF (NIRT and IRT), MURI-ARO, MURI-ONR, ChevronTexaco, Dow Corning, Intel, Nissan Corp, Aventis Pharma, Berlex Biopharma, Boehringer-Ingelheim, Pfizer and Allozyne.
Funding AgencyGrant Number
Army Research Office (ARO)UNSPECIFIED
Office of Naval Research (ONR)UNSPECIFIED
Department of Energy (DOE)UNSPECIFIED
Berlex BiopharmaUNSPECIFIED
Subject Keywords:G protein-coupled receptors; Mrg receptors; Adenine; Docking; HierDock
Issue or Number:4
PubMed Central ID:PMC2151207
Record Number:CaltechAUTHORS:20190226-155229153
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Official Citation:Jiyoung Heo, Nagarajan Vaidehi, John Wendel, William A. Goddard, Prediction of the 3-D structure of rat MrgA G protein-coupled receptor and identification of its binding site, Journal of Molecular Graphics and Modelling, Volume 26, Issue 4, 2007, Pages 800-812, ISSN 1093-3263, (
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:93278
Deposited By: Tony Diaz
Deposited On:26 Feb 2019 23:58
Last Modified:03 Oct 2019 20:52

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