Advances in receptor conformation research: the quest for functionally selective conformations focusing on the...

Seven-transmembrane receptors, also called GPCRs, represent the largest class of drug targets. Upon ligand binding, a GPCR undergoes conformational rearrangement and thereby changes its interaction with effector proteins including the cognate G-proteins and the multifunctional adaptor proteins, β-arrestins. These proteins, by initiating distinct signal transduction mechanisms, mediate one or several functional responses. Recently, the concept of ligand-directed GPCR signalling, also called functional selectivity or biased agonism, has been proposed to explain the phenomenon that chemically diverse ligands exhibit different efficacies towards the different signalling pathways of a single GPCR, and thereby act as functionally selective or 'biased' ligands. Current concepts support the notion that ligand-specific GPCR conformations are the basis of ligand-directed signalling. Multiple studies using fluorescence spectroscopy, X-ray crystallography, mass spectroscopy, nuclear magnetic resonance spectroscopy, single-molecule force spectroscopy and other techniques have provided the evidence to support this notion. It is anticipated that these techniques will ultimately help elucidate the structural basis of ligand-directed GPCR signalling at a precision meaningful for structure-based drug design and how a specific ligand molecular structure induces a unique receptor conformation leading to biased signalling. In this review, we will summarize recent advances in experimental techniques applied in the study of functionally selective GPCR conformations and breakthrough data obtained in these studies particularly those of the β2-adrenoceptor.