Structural Insights into the Unique Modes of Relaxin-Binding and Tethered-Agonist Mediated Activation of RXFP1 and RXFP2.

Autor:	Sethi A; Department of Biochemistry & Pharmacology, The University of Melbourne, Parkville, Victoria 3052, Australia; Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria 3052, Australia., Bruell S; Department of Biochemistry & Pharmacology, The University of Melbourne, Parkville, Victoria 3052, Australia; Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Victoria 3052, Australia., Ryan T; Australian Nuclear Science Technology Organisation, The Australian Synchrotron, 800 Blackburn Rd, Clayton, Victoria 3168, Australia., Yan F; Department of Biochemistry & Pharmacology, The University of Melbourne, Parkville, Victoria 3052, Australia; Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria 3052, Australia., Tanipour MH; Department of Biochemistry & Pharmacology, The University of Melbourne, Parkville, Victoria 3052, Australia; Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria 3052, Australia., Mok YF; Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria 3052, Australia., Draper-Joyce C; Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Victoria 3052, Australia., Khandokar Y; Department of Biochemistry & Pharmacology, The University of Melbourne, Parkville, Victoria 3052, Australia; Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria 3052, Australia., Metcalfe RD; Department of Biochemistry & Pharmacology, The University of Melbourne, Parkville, Victoria 3052, Australia; Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria 3052, Australia., Griffin MDW; Department of Biochemistry & Pharmacology, The University of Melbourne, Parkville, Victoria 3052, Australia; Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria 3052, Australia., Scott DJ; Department of Biochemistry & Pharmacology, The University of Melbourne, Parkville, Victoria 3052, Australia; Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Victoria 3052, Australia., Hossain MA; Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Victoria 3052, Australia; School of Chemistry, The University of Melbourne, Parkville, Victoria 3052, Australia., Petrie EJ; Department of Biochemistry & Pharmacology, The University of Melbourne, Parkville, Victoria 3052, Australia; Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria 3052, Australia; Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Victoria 3052, Australia., Bathgate RAD; Department of Biochemistry & Pharmacology, The University of Melbourne, Parkville, Victoria 3052, Australia; Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Victoria 3052, Australia. Electronic address: bathgate@florey.edu.au., Gooley PR; Department of Biochemistry & Pharmacology, The University of Melbourne, Parkville, Victoria 3052, Australia; Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria 3052, Australia. Electronic address: prg@unimelb.edu.au.
Jazyk:	angličtina
Zdroj:	Journal of molecular biology [J Mol Biol] 2021 Oct 15; Vol. 433 (21), pp. 167217. Date of Electronic Publication: 2021 Aug 26.
DOI:	10.1016/j.jmb.2021.167217
Abstrakt:	Our poor understanding of the mechanism by which the peptide-hormone H2 relaxin activates its G protein coupled receptor, RXFP1 and the related receptor RXFP2, has hindered progress in its therapeutic development. Both receptors possess large ectodomains, which bind H2 relaxin, and contain an N-terminal LDLa module that is essential for receptor signaling and postulated to be a tethered agonist. Here, we show that a conserved motif (GDxxGWxxxF), C-terminal to the LDLa module, is critical for receptor activity. Importantly, this motif adopts different structures in RXFP1 and RXFP2, suggesting distinct activation mechanisms. For RXFP1, the motif is flexible, weakly associates with the LDLa module, and requires H2 relaxin binding to stabilize an active conformation. Conversely, the GDxxGWxxxF motif in RXFP2 is more closely associated with the LDLa module, forming an essential binding interface for H2 relaxin. These differences in the activation mechanism will aid drug development targeting these receptors. Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (Copyright © 2021 Elsevier Ltd. All rights reserved.)
Databáze:	MEDLINE
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