What is biased efficacy? Defining the relationship between intrinsic efficacy and free energy coupling.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Onaran, HO; Rajagopal, S; Costa, T

Published Date

  • December 2014

Published In

Volume / Issue

  • 35 / 12

Start / End Page

  • 639 - 647

PubMed ID

  • 25448316

Pubmed Central ID

  • 25448316

Electronic International Standard Serial Number (EISSN)

  • 1873-3735

Digital Object Identifier (DOI)

  • 10.1016/j.tips.2014.09.010

Language

  • eng

Conference Location

  • England