Elucidation of relaxin-3 binding interactions in the extracellular loops of RXFP3

Bathgate, Ross A. D., Oh, Maria H. Y., Ling, W. J. Jason, Kaas, Quentin, Hossain, M. Akhter, Gooley, Paul R. and Rosengren, K. Johan (2013) Elucidation of relaxin-3 binding interactions in the extracellular loops of RXFP3. Frontiers in Endocrinology, 4 FEB: . doi:10.3389/fendo.2013.00013

Author Bathgate, Ross A. D.
Oh, Maria H. Y.
Ling, W. J. Jason
Kaas, Quentin
Hossain, M. Akhter
Gooley, Paul R.
Rosengren, K. Johan
Title Elucidation of relaxin-3 binding interactions in the extracellular loops of RXFP3
Journal name Frontiers in Endocrinology   Check publisher's open access policy
ISSN 1664-2392
Publication date 2013
Sub-type Article (original research)
DOI 10.3389/fendo.2013.00013
Open Access Status DOI
Volume 4
Issue FEB
Total pages 10
Place of publication Lausanne, Switzerland
Publisher Frontiers Research Foundation
Collection year 2014
Language eng
Subject 2712 Endocrinology, Diabetes and Metabolism
Abstract Relaxin-3 is a highly conserved neuropeptide in vertebrate species and binds to the Class A G protein-coupled receptor (GPCR) RXFP3. Relaxin-3 is involved in a wide range of behaviors, including feeding, stress responses, arousal, and cognitive processes and therefore targeting of RXFP3 may be relevant for a range of neurological diseases. Structural knowledge of RXFP3 and its interaction with relaxin-3 would both increase our understanding of ligand recognition in GPCRs that respond to protein ligands and enable acceleration of the design of drug leads. In this study we have used comparative sequence analysis, molecular modeling and receptor mutagenesis to investigate the binding site of the native ligand human relaxin-3 (H3 relaxin) on the human RXFP3 receptor. Previous structure function studies have demonstrated that arginine residues in the H3 relaxin B-chain are critical for binding interactions with the receptor extracellular loops and/or N-terminal domain. Hence we have concentrated on determining the ligand interacting sites in these domains and have focused on glutamic (E) and aspartic acid (D) residues in these regions that may form electrostatic interactions with these critical arginine residues. Conserved D/E residues identified from vertebrate species multiple sequence alignments were mutated to Ala in human RXFP3 to test the effect of loss of amino acid side chain on receptor binding using a Eu-labeled relaxin-3 agonist. Finally data from mutagenesis experiments have been used in ligand docking simulations to a homology model of human RXFP3 based on the peptide-bound chemokine receptor 4 (CXCR4) structure. These studies have resulted in a model of the relaxin-3 interaction with RXFP3 which will inform further interrogation of the agonist binding site.
Keyword Modeling
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2014 Collection
School of Biomedical Sciences Publications
Institute for Molecular Bioscience - Publications
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