Journal article

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

Ashish Sethi, Shoni Bruell, Tim Ryan, Fei Yan, Mohammad Hossein Tanipour, Yee-Foong Mok, Chris Draper-Joyce, Yogesh Khandokar, Riley D Metcalfe, Michael DW Griffin, Daniel J Scott, Mohammad Akhter Hossain, Emma J Petrie, Ross AD Bathgate, Paul R Gooley

JOURNAL OF MOLECULAR BIOLOGY | ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD | Published : 2021

Abstract

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 mod..

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Grants

Awarded by National Health and Medical Research Council of Australia


Awarded by NHMRC Research Fellowship


Funding Acknowledgements

This research was supported by National Health and Medical Research Council of Australia project grant 1100676 (R.A.D.B., D.J.S, M.D.W.G and P. R.G.). We acknowledge the facilities and technical assistance of the NMR facility (University of Melbourne), the Australian Synchrotron, part of the Australian Nuclear Science and Technology Organisation, for the provision of beamtime, and the beamline staff at the SAXS/WAXS beamlines and the Victorian Government Operational Infrastructure Support Program. R.A.D.B. is supported by an NHMRC Research Fellowship (1042650).