G protein activation by G protein coupled receptors: ternary complex formation or catalyzed reaction?

Biochem Pharmacol. 2004 Sep 1;68(5):799-806. doi: 10.1016/j.bcp.2004.05.044.

Abstract

G protein coupled receptors catalyze the GDP/GTP exchange on G proteins, thereby activating them. The ternary complex model, designed to describe agonist binding in the absence of GTP, is often extended to G protein activation. This is logically unsatisfactory as the ternary complex does not accumulate when G proteins are activated by GTP. Extended models taking into account nucleotide binding exist, but fail to explain catalytic G protein activation. This review puts forward an enzymatic model of G protein activation and compares its predictions with the ternary complex model and with observed receptor phenomenon. This alternative model does not merely provide a new set of formulae but leads to a new philosophical outlook and more readily accommodates experimental observations. The ternary complex model implies that, HRG being responsible for efficient G protein activation, it should be as stable as possible. In contrast, the enzyme model suggests that although a limited stabilization of HRG facilitates GDP release, HRG should not be "too stable" as this might trap the G protein in an inactive state and actually hinder G protein activation. The two models also differ completely in the definition of the receptor "active state": the ternary complex model implies that the active state corresponds to a single active receptor conformation (HRG); in contrast, the catalytic model predicts that the active receptor state is mobile, switching smoothly through various conformations with high and low affinities for agonists (HR, HRG, HRGGDP, HRGGTP, etc.).

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Catalysis
  • GTP-Binding Proteins / metabolism*
  • Guanosine Diphosphate / metabolism
  • Guanosine Triphosphate / metabolism
  • Heterotrimeric GTP-Binding Proteins / metabolism
  • Humans
  • Kinetics
  • Models, Chemical
  • Protein Conformation
  • Receptors, G-Protein-Coupled / metabolism*
  • Signal Transduction / physiology

Substances

  • Receptors, G-Protein-Coupled
  • Guanosine Diphosphate
  • Guanosine Triphosphate
  • GTP-Binding Proteins
  • Heterotrimeric GTP-Binding Proteins