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

Publication ,  Journal Article
Onaran, HO; Rajagopal, S; Costa, T
Published in: Trends Pharmacol Sci
December 2014

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.

Duke Scholars

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Published In

Trends Pharmacol Sci

DOI

EISSN

1873-3735

Publication Date

December 2014

Volume

35

Issue

12

Start / End Page

639 / 647

Location

England

Related Subject Headings

  • Thermodynamics
  • Receptors, G-Protein-Coupled
  • Pharmacology & Pharmacy
  • Kinetics
  • 3214 Pharmacology and pharmaceutical sciences
  • 11 Medical and Health Sciences
  • 06 Biological Sciences
 

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Onaran, H. O., Rajagopal, S., & Costa, T. (2014). What is biased efficacy? Defining the relationship between intrinsic efficacy and free energy coupling. Trends Pharmacol Sci, 35(12), 639–647. https://doi.org/10.1016/j.tips.2014.09.010
Onaran, H Ongun, Sudarshan Rajagopal, and Tommaso Costa. “What is biased efficacy? Defining the relationship between intrinsic efficacy and free energy coupling.Trends Pharmacol Sci 35, no. 12 (December 2014): 639–47. https://doi.org/10.1016/j.tips.2014.09.010.
Onaran HO, Rajagopal S, Costa T. What is biased efficacy? Defining the relationship between intrinsic efficacy and free energy coupling. Trends Pharmacol Sci. 2014 Dec;35(12):639–47.
Onaran, H. Ongun, et al. “What is biased efficacy? Defining the relationship between intrinsic efficacy and free energy coupling.Trends Pharmacol Sci, vol. 35, no. 12, Dec. 2014, pp. 639–47. Pubmed, doi:10.1016/j.tips.2014.09.010.
Onaran HO, Rajagopal S, Costa T. What is biased efficacy? Defining the relationship between intrinsic efficacy and free energy coupling. Trends Pharmacol Sci. 2014 Dec;35(12):639–647.
Journal cover image

Published In

Trends Pharmacol Sci

DOI

EISSN

1873-3735

Publication Date

December 2014

Volume

35

Issue

12

Start / End Page

639 / 647

Location

England

Related Subject Headings

  • Thermodynamics
  • Receptors, G-Protein-Coupled
  • Pharmacology & Pharmacy
  • Kinetics
  • 3214 Pharmacology and pharmaceutical sciences
  • 11 Medical and Health Sciences
  • 06 Biological Sciences