title: What is biased efficacy? Defining the relationship between intrinsic efficacy and free energy coupling.
abstract: A G protein-coupled receptor (GPCR) is only biologically active when associated with a transduction protein, but it can also switch function by interacting with different types of transduction proteins. Biased agonism arises when the ligand induces the receptor to engage distinct transduction proteins with different efficacies. We briefly review the concept of ligand efficacy, from the classical empirical idea to the current mechanistic views of allosteric regulation in proteins. A combination of these theoretically distinct ideas and methodologies allows us to distinguish true ligand bias from divergences of signalling caused by the system. We also demonstrate a rigorous mathematical connection between the intrinsic efficacy of classical receptor theory and the energetic effect that makes a ligand capable of stabilizing receptor-transducer association in the ternary complex model. This relationship unifies different definitions of efficacy and provides a rational basis for quantifying biased agonism.
authors.affiliation: Department of Pharmacology, Ankara University Faculty of Medicine, Ankara, Turkey.
authors.forename: H Ongun
authors.initials: HO
authors.lastname: Onaran
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham NC, USA.
authors.forename: Sudarshan
authors.initials: S
authors.lastname: Rajagopal
authors.affiliation: Department of Pharmacology, Istituto Superiore di Sanità, Rome, Italy. Electronic address: tomcosta@iss.it.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Costa
mesh_terms: D007700:Kinetics; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000737:chemistry* / Q000378:metabolism*; D013816:Thermodynamics
chemical_list: D043562:Receptors, G-Protein-Coupled
keywords: GPCR