Class B G protein coupled receptors (GPCRs) are activated by large peptide hormones and are important drug targets in many human diseases including metabolic, neurodegenerative and cardiovascular diseases. Like most GPCRs, these receptors are pleiotropically coupled with the physiological impacts of receptor activation dependent on the spectrum of signalling and regulatory events initiated by ligand binding. The canonical signalling pathway for class B GPCRs is through coupling to heterotrimeric Gs proteins resulting in cAMP mediated signalling. Peptide hormones achieve this through interacting with their receptors via a common two-domain binding mechanism, however the molecular details for these interactions and how this results in receptor activation and promotes G protein coupling is not fully understood. Our work aims to understand at the structural level how peptide agonists bind to their receptors and enable them to couple to their preferred G protein to initiate intracellular signalling.
Using single particle cryo electron microscopy, we have solved the structures of two class B GPCRs in complex with a peptide agonist and heterotrimeric Gs. Coupled with molecular and pharmacological techniques, these structures provide key mechanistic insights into the mechanism of action of this important class of GPCRs. Collectively, this work is starting to provide novel insights into class B receptor structure and function that might be exploited for the development of novel therapeutics.