Structure of the R3/I5 chimeric relaxin peptide, a selective GPCR135 and GPCR142 agonist

Haugaard-Jönsson, Linda M., Hossain, Mohammed Akhter, Daly, Norelle L., Bathgate, Ross A. D., Wade, John D., Craik, David J. and Rosengren, K. Johan (2008) Structure of the R3/I5 chimeric relaxin peptide, a selective GPCR135 and GPCR142 agonist. The Journal of Biological Chemistry, 283 35: 23811-23818. doi:10.1074/jbc.M800489200

Author Haugaard-Jönsson, Linda M.
Hossain, Mohammed Akhter
Daly, Norelle L.
Bathgate, Ross A. D.
Wade, John D.
Craik, David J.
Rosengren, K. Johan
Title Structure of the R3/I5 chimeric relaxin peptide, a selective GPCR135 and GPCR142 agonist
Formatted title
Structure of the R3/I5 chimeric relaxin peptide, a selective GPCR135 and GPCR142 agonist
Journal name The Journal of Biological Chemistry   Check publisher's open access policy
ISSN 1067-8816
ISBN 978-1-57331-721-4
Publication date 2008-08-29
Year available 2008
Sub-type Article (original research)
DOI 10.1074/jbc.M800489200
Open Access Status DOI
Volume 283
Issue 35
Start page 23811
End page 23818
Total pages 7
Place of publication Bethesda, U.S.
Publisher American Society for Biochemistry and Molecular Biology
Language eng
Subject C1
030401 Biologically Active Molecules
860899 Human Pharmaceutical Products not elsewhere classified
0304 Medicinal and Biomolecular Chemistry
Abstract The human relaxin family comprises seven peptide hormones with various biological functions mediated through interactions with G-protein-coupled receptors. Interestingly, among the hitherto characterized receptors there is no absolute selectivity toward their primary ligand. The most striking example of this is the relaxin family ancestor, relaxin-3, which is an agonist for three of the four currently known relaxin receptors: GPCR135, GPCR142, and LGR7. Relaxin-3 and its endogenous receptor GPCR135 are both expressed predominantly in the brain and have been linked to regulation of stress and feeding. However, to fully understand the role of relaxin-3 in neurological signaling, the development of selective GPCR135 agonists and antagonists for in vivo studies is crucial. Recent reports have demonstrated that such selective ligands can be achieved by making chimeric peptides comprising the relaxin-3 B-chain combined with the INSL5 A-chain. To obtain structural insights into the consequences of combining A- and B-chains from different relaxins we have determined the NMR solution structure of a human relaxin-3/INSL5 chimeric peptide. The structure reveals that the INSL5 A-chain adopts a conformation similar to the relaxin-3 A-chain, and thus has the ability to structurally support a native-like conformation of the relaxin-3 B-chain. These findings suggest that the decrease in activity at the LGR7 receptor seen for this peptide is a result of the removal of a secondary LGR7 binding site present in the relaxin-3 A-chain, rather than conformational changes in the primary B-chain receptor binding site.
Keyword Receptor-binding
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID 350284
Institutional Status UQ
Additional Notes First published on June 24, 2008.

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Created: Thu, 16 Apr 2009, 01:14:31 EST by Cody Mudgway on behalf of Institute for Molecular Bioscience