Objective

Recent years have witnessed some dramatic advances in the approaches available for GPCR drug discovery. High resolution X-ray structures are now available for more than 50 GPCRs, allowing the mechanisms of activation to be deduced, and enabling structure-based drug discovery approaches to be used for the first time. To enable structural studies of GPCRs Heptares have developed the StaR technology, where the introduction of a small number of mutations locks the GPCR in an active or inactive state and stabilises the receptor sufficiently to allow purification and crystallization. X-ray structures are now available for class A, B and C receptors, in some cases with a range of ligands bound. This has enabled several interesting new features of GPCR structure and ligand recognition to be identified. Of particular interest has been the number of examples where compounds are found to bind in allosteric sites. In some cases this was anticipated, in others it was a complete surprise. Structures of GPCRs with modulators are now enabling the range of mechanisms by which GPCRs can be regulated allosterically to be deduced. In addition to structural studies, the StaR approach enables other biophysical approaches such as surface plasmon resonance to investigate ligand binding. This has allowed the residues contributing to ligand binding to be identified, in the absence of detailed X-ray structures, as well as the kinetics of ligand binding to be determined