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

A Sethi; S Bruell; N Patil; MA Hossain; DJ Scott; EJ Petrie; RAD Bathgate; PR Gooley

Journal article

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

A Sethi, S Bruell, N Patil, MA Hossain, DJ Scott, EJ Petrie, RAD Bathgate, PR Gooley

Nature Communications | Published : 2016

DOI: 10.1038/ncomms11344

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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 bi..

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University of Melbourne Researchers

Akhter Hossain Author

Daniel Scott Author

Ross Bathgate Author

Paul Gooley Author

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Grants

Awarded by National Science Foundation

Funding Acknowledgements

We thank Tania Ferraro and Sharon Layfield for technical assistance; Jingbo Xiao, Juan Marugan (NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, MD, USA) and Alexander Agoulnik (Department of Cellular Biology and Pharmacology, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA) for the kind gift of ML290. This research was supported by National Health and Medical Research Council of Australia project grants (628427) and (1043750; R.A.D.B. and P.R.G.), the Victorian Government Operational Infrastructure Support Program and equipment grants from the Australian Research Council (LE120100022). R.A.D.B. is supported by an NHMRC Research Fellowship.