Understanding the structural basis of Class B GPCR function
Class B G protein-coupled receptors (GPCRs) respond to paracrine or endocrine peptide hormones and are involved in the physiology or pathophysiology of bone homeostasis, glucose regulation, satiety & gastro-intestinal function as well as pain transmission. As a result these receptors are targets for existing drugs that treat osteoporosis, hypercalcaemia, Paget’s disease and type II diabetes and are being actively pursued as targets for other diseases. These diseases represent a significant global health burden, however the therapeutic potential of these receptors is underutilised. There are currently high attrition rates in developing suitable small molecule drugs that target these receptors that speak to a lack of mechanistic understanding of how these receptors work. Understanding receptor structure, how ligands bind and the dynamic changes that lead to selective engagement of signalling is critical to drug design and effective control of disease.
We offer a number of projects in this area that use a range of approaches to understand Class B GPCR function, including protein mutagenesis, use of biochemical and biophysical techniques to examine receptor complexes and receptor dynamics, high end microsopic imaging and x-ray crystallography to generate high resolution structural data of stable conformations. In addition, we also combine this work with 3D protein modelling to understand drug and natural ligand docking and how specific receptor residues contribute to downstream receptor signalling.