Studies on G protein-coupled receptors; structure, function and drug development

The largest single class of drug targets is the G Protein-Coupled Receptor (GPCR) family, which were targets for 13 of the top 50 prescription drugs sold in the U.S.A. in 2010 (26%). 

Modern GPCR drug development is encumbered by a lack of information about the molecular structure underlying GPCR function and the reliance on cell-based assays that are prone to false positives in drug screening. The fundamental importance of GPCRs is highlighted by the 2012 Nobel Prize in Chemistry awarded to Kobilka and Lefkowitz for their research into the molecular mechanisms of GPCR function. Our group uses a multidisciplinary approach to study GPCR function and is targeting numerous important GPCRs for drug development.  One class of receptors we are studying are the relaxin family peptide receptors RXFP1-4. The ligands for these GPCRs are the peptides relaxin (RXFP1), insulin-like peptide 3 (INSL3) (RXFP2), relaxin-3 (RXFP3), and INSL5 (RXFP4). Relaxin is a hormone and growth factor that induces its effects by regulating collagen turnover, stimulating tissue growth and angiogenesis and inducing blood vessel dilatation. It recently passed a successful Phase III clinical trial for the treatment of acute heart failure being performed by Novartis (Switzerland). INSL3 is essential for germ cell maturation and drugs targeting its receptor RXFP2 have considerable potential as fertility regulators in both males and females. INSL5 is a gut hormone that has potential roles in appetite regulation and we are working with Takeda Cambridge to develop compounds targeting its receptor RXFP4 which may be useful for treating feeding disorders.

Relaxin-3 is a specific neuropeptide which our laboratory recently discovered and has potential roles in regulating behaviours which are perturbed in mental illnesses including anxiety, depression, sleep disorders, and memory deficits. Hence drugs targeting the relaxin-3 receptor RXFP3 may be potential therapeutics to treat these mental illnesses. We are working with pharmaceutical industry partners (eg. Takeda and Novartis) to determine the biological roles of the peptides and to develop drugs targeting their receptors.  We are using various molecular and pharmacological techniques to map the native ligand binding sites of these receptors and determine the mechanisms of receptor activation as well their cell signalling characteristics. A complete understanding of the mechanism of ligand binding and activation is required to design drugs targeting these receptors. Furthermore in collaboration with Dr Daniel Scott and A/Prof Paul Gooley (Bio21) we are utilizing various biochemical techniques to study the receptor structures.

The ability to probe these receptors using biochemical and structural approaches enhances our understanding of how they function and will lead to the discovery and optimisation of novel therapeutics. We are therefore studying ligand interactions with receptor domains using soluble protein constructs and NMR. Additionally, we are one of the only laboratories in the world using protein engineering techniques to generate stabilised GPCRs that can be readily applied to standard biochemical methods after they have been removed from the cell membrane (see Projects from Dr Daniel Scott).   We are using these stabilised receptors to probe the structure and dynamics of GPCRs with X-ray crystallography and NMR as well as protein interaction analysis and screening to investigate how these receptors bind to natural ligands and drugs.  

Project Overview - Honours, Masters and PhD projects are available to study the molecular pharmacology of these novel GPCRs. Candidates will undergo training in various techniques including molecular cloning, site-directed mutagenesis, cell biology, cell signalling, protein chemistry, protein engineering, fluorescence activated cell sorting (FACS) and confocal microscopy.

Kong RCK, Petrie EJ, Mohanty B, Ling J, Lee JCY, Gooley PR and Bathgate RAD (2013) RXFP1 utilises hydrophobic moieties on a signalling surface of the LDLa module to mediate receptor activation. Journal of Biological Chemistry 288: 28138-28151

Bathgate RAD, Oh MHY, Ling WJJ, Kaas Q, Hossain MA, Gooley PR and Rosengren KJ (2013)  Elucidation of relaxin-3 binding interactions in the extracellular loops of RXFP3. Frontiers in Endocrinology. Article 13

Bathgate RAD, et al. (2012) Relaxin Family Peptides and Their Receptors. Physiological Reviews. 93: 405–480 

Scott DJ, Rosengren KJ and Bathgate RAD (2012) Determining the factors that govern INSL3 binding specificity to RXFP2. Molecular Endocrinology. 26: 1896-1906  

Callander GE, Thomas WG and Bathgate RAD (2009) Prolonged RXFP1 and RXFP2 signaling can be explained by poor internalization and a lack of βarrestin recruitment. American Journal of Physiology, Cell Physiology 296: C1058-66

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