Novel tools to study the relaxin-3 signalling system

Cell-cell communication via endogenous peptides and their receptors is vital for controlling all aspects of human physiology. Neuropeptides in the brain are especially important in controlling most human behaviours and mediate their actions by binding to cell surface G protein-coupled receptors (GPCRs), which are the most common pharmacological drug targets to treat a wide range of diseases. The relaxin family peptide receptor-3 (RXFP3) is a GPCR which together with its neuropeptide ligand relaxin-3 is primarily expressed in the brain, and forms a system that regulates several physiological processes such as food intake, stress responses, arousal, exploratory behaviors, spatial learning and memory as well as cognition. RXFP3 has great potential as a drug target for the treatment of neurological diseases, however, development of drugs targeting this receptor has been hindered by limited information on the protein target and lack of lead drugs that are able to penetrate the brain and demonstrate drug action in animal models. Dr. Predrag Kalaba, from the Muttenthaler Lab, Institute of Biological Chemistry will join the Laboratory of Ross Bathgate and his multidisciplinary team at the Florey Institute, Melbourne, Australia with an aim to develop RXFP3-selective small molecules drug leads that will serve as pharmacological tools to validate RXFP3 as a target for the treatment of neurological diseases. They will apply cutting-edge structural biology strategies that will provide structural insights into the RXFP3 protein for the first time and guide drug design. The combination of advanced computational methods, modern chemical synthesis, novel approaches to GPCR production and state-of-the art structural biology will facilitate the development of specific RXFP3 small molecule drug leads. There are very few international groups that have the collective expertise, cutting- edge techniques, and platform technologies required to undertake the outlined ambitious project. Dr. Kalaba will be fully trained in the workflow of GPCR directed evolution, enhanced protein expression and cryo-EM structural characterisation such that, upon his return to the University of Vienna he can establish these techniques for the structural determination of any GPCR or indeed other membrane proteins. The Muttenthaler Lab and the Institute of Biological Chemistry will significantly gain from this knowledge transfer, allowing them to utilise their vast experience in GPCR ligand design as well as protein semi-synthesis and link it to the latest GPCR structural biology techniques.