How does relaxin activate its G-protein coupled receptor?

  • Project Leader

    Associate Professor Paul Gooley
    T: +61 0437 835 059 (mobile)
    +61 3 834 42273

    E: prg@unimelb.edu.au
    W: Personal web page

    Location: Rm 231, Level 02, Bio21 Institute, 30 Flemington Rd

Project Details

diagram showing model of RXFP1 activation
Figure 1: Model of RXFP1 activation


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.  We have recently published that the linker 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, why this is also remains unclear. This project therefore will continue to identify how the LDLa module and linker combine to activate RXFP1. We wish to understand more clearly which residues of relaxin interact with the linker. We want to solve the structure of the ectodomain bound to relaxin. In addition we wish to identify where on the transmembrane domain the linker residues and LDLa module or linker residues 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.

Collaborators

Professor Ross Bathgate, Dr Dan Scott, Dr Akhter Hossain (Florey)

Research Opportunities

This research project is available to PhD, Honours students to join as part of their thesis.
Please contact the Research Group Leader to discuss your options.

Research Publications

Sethi A, Bruell S, Patil N, Hossain MA, Scott DJ, Petrie EJ, Bathgate RAD, Gooley, PR. The complex binding mode of the peptide hormone H2 relaxin to its receptor RXFP1. Nature Communications 2016; 7: 11344.

Research Group

Gooley laboratory: Structural biology of disease



Faculty Research Themes

Neuroscience

School Research Themes

Biomedical Neuroscience, Cellular Imaging & Structural Biology



Key Contact

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

Department / Centre

Biochemistry and Molecular Biology

Unit / Centre

Gooley laboratory: Structural biology of disease