Resolving and targeting the complex molecular mechanisms underlying GPCR signalling

  • Bathgate, Ross (Primary Chief Investigator (PCI))
  • Scott, Daniel J (Chief Investigator (CI))
  • Gooley, Paul Raymond (Chief Investigator (CI))
  • Griffith, Michael (Chief Investigator (CI))
  • Chalmers, David (Chief Investigator (CI))
  • Hubbard, Roderick (Chief Investigator (CI))

Project: Research

Project Description

G protein-coupled receptors (GPCRs) are sensory membrane proteins located on the surface of all human cell types. GPCRs are the largest class of drug targets, yet the majority remain undrugged, often despite clear linkage to disease. A lack of structural knowledge about how ligands engage GPCRs to modulate complex signalling events has hindered compound optimisation in drug discovery. GPCRs are typically capable of stimulating diverse signaling outputs depending on the bound ligand and the cellular environment. This diverse signalling has implications for drug discovery, where particular pathways activated by a receptor may be beneficial, whereas others may cause detrimental side effects. Recent crystal structures of inactive- and active-state GPCRs give us snapshots of how diverse ligands interact with GPCRs and the global conformational changes that occur upon receptor activation. However, recent NMR work by Nobel laureates Kobilka and Wüthrich show that the prototypical GPCR, β2-adrenoceptor, exists in an ensemble of states, with different ligands shifting this equilibrium in different ways upon binding, to influence signaling. This work needs to be expanded, and applied to other GPCRs of interest to facilitate drug discovery. We have successfully: stabilised; isotopically labelled; and analysed with NMR three prototypical GPCRs: the peptide receptor neurotensin receptor 1 (NTS1); the catecholamine receptor α1A-adrenoceptor (α1A-AR); and its closely related subtype α1B-AR. In this proposal we will gain atomic resolution insights into: the existence of intermediate GPCR states and their roles; the kinetics governing receptor conformational change; and how full, partial or biased agonists modulate receptor conformations and dynamics to influence signalling outputs. This work will establish an approach for structure-based drug discovery at GPCRs to increase the national research capacity by providing new tools for the many GPCR laboratories in the country to use.
StatusActive
Effective start/end date1/01/1831/12/21