The Role Of G-Protein-Coupled Receptor Activation By Conformational Selection As Revealed By Single-Molecule Fluorescence

G-protein-coupled receptors (GPCRs) are the largest class of transmembrane proteins, making them an attractive target for therapeutics. At the heart of drug discovery is understanding the structural implications that ligands pose on the activation states of receptors. Two models are typically used to explain the mechanistic basis of ligand-activation: induced-fit and conformational selection. Recent evidence from our groups and others (Ye, L. et al., Nature 533,265-268, May 2016) incline towards the second model, suggesting the coexistence of multiple receptor states, which, depending on the nature of the ligand bound, i.e., full, partial or inverse agonist, will be more or less populated.