How Does Relaxin Activate its G-protein Coupled Receptor?

  • Project Leader

    Associate Professor Paul Gooley
    T: +61 3 8344 2273
    E: prg@unimelb.edu.au
    W: Personal web page

    Location: 402, Level 04, Bio21 Institute, 30 Flemington Rd, Parkville

Project Details

Relaxin is an important hormone that is currently in clinical trials for treating acute heart failure. As it is necessary to inject relaxin and as relaxin is rapidly cleared, the design of small molecule agonists has become important. Relaxin belongs to the insulin superfamily and thus is a two chain disulphide linked peptide. Relaxin activates the GPCR, RXFP1, an unusual class A GPCR that comprises a large ectodomain with an N-terminal LDLa module joined by a putatively unstructured 32-residue linker to a Leucine Rich Repeat (LRR) domain. Truncation of the LDLa module results in a receptor that cannot activate, indicating that the LDLa module may be the true ligand. Previous research suggested that relaxin binds by its B-chain to the LRR domain resulting in an uncharacterized conformational change whereby the LDLa module bound and activated the transmembrane domain. Recent unpublished investigations by us have shown critical roles for the linker, where it also forms a part of the relaxin binding site. We think relaxin binds via its A-chain to the linker, inducing a structure within the linker, and that this is the key conformational change. Importantly a series of residues immediately C-terminal to the LDLa module while not playing a direct role in ligand binding, perturb binding when mutated, although we do not know how. Furthermore these residues if mutated show significant loss of receptor activation, where this is also unknown. This project therefore will continue to identify how the LDLa module and linker combine to activate RXFP1. We wish to understand the structure of the linker including the relaxin binding site and how this site changes on binding relaxin. We will characterize the structural changes and how the residues C-terminal to the LDLa module activate the receptor. In addition we wish to identify where on the transmembrane domain the linker residues and LDLa module interact. This structural understanding will aid the development of novel agonists of RXFP1. Towards this end we will make novel peptide constructs to antagonize or agonize the relaxin-RXFP1 interaction. Parallel investigations will be applied to the related INSL3-RXFP2 system.

model showing RXFP! activation

Research Group

Gooley Laboratory: Structural Biology of Disease



Faculty Research Themes

Neuroscience

School Research Themes

Neuroscience, Molecular Mechanisms of Disease, Cellular Imaging & Structural Biology



Key Contact

For further information about this research, please contact the research group leader.

Department / Centre

Biochemistry and Molecular Biology