The complex binding mode of the peptide hormone H2 relaxin to its receptor RXFP1

Ashish Sethi, Shoni Bruell, Nitin Patil, Mohammed Akhter Hossain, Daniel J. Scott, Emma J. Petrie, Ross A. D. Bathgate () and Paul R. Gooley ()
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Ashish Sethi: The University of Melbourne
Shoni Bruell: The University of Melbourne
Nitin Patil: Florey Institute of Neuroscience and Mental Health, The University of Melbourne
Mohammed Akhter Hossain: Florey Institute of Neuroscience and Mental Health, The University of Melbourne
Daniel J. Scott: The University of Melbourne
Emma J. Petrie: The University of Melbourne
Ross A. D. Bathgate: The University of Melbourne
Paul R. Gooley: The University of Melbourne

Nature Communications, 2016, vol. 7, issue 1, 1-12

Abstract: Abstract H2 relaxin activates the relaxin family peptide receptor-1 (RXFP1), a class A G-protein coupled receptor, by a poorly understood mechanism. The ectodomain of RXFP1 comprises an N-terminal LDLa module, essential for activation, tethered to a leucine-rich repeat (LRR) domain by a 32-residue linker. H2 relaxin is hypothesized to bind with high affinity to the LRR domain enabling the LDLa module to bind and activate the transmembrane domain of RXFP1. Here we define a relaxin-binding site on the LDLa-LRR linker, essential for the high affinity of H2 relaxin for the ectodomain of RXFP1, and show that residues within the LDLa-LRR linker are critical for receptor activation. We propose H2 relaxin binds and stabilizes a helical conformation of the LDLa-LRR linker that positions residues of both the linker and the LDLa module to bind the transmembrane domain and activate RXFP1.

Date: 2016
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DOI: 10.1038/ncomms11344

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