The Allosteric Mechanism of G‐Protein‐Coupled Receptors is Induced Fit, Not Conformational Selection

TL;DR

This paper shows that GPCRs use an induced-fit mechanism, where ligands bind to inactive receptor states before the receptor changes shape.

Contribution

The study provides evidence that the allosteric mechanism in GPCRs is induced fit, not conformational selection.

Findings

Stopped-flow and NMR experiments support induced fit in the neurotensin receptor 1.

Ligand association rates decrease in the β2-adrenergic receptor when active conformations are stabilized.

A closed ligand-binding site in active GPCR conformations supports the induced-fit mechanism.

Abstract

The allosteric mechanism of G‐protein‐coupled receptors (GPCRs) involves a population shift from inactive to active receptor conformations in response to the binding of ligand agonists. Two possible kinetic mechanisms for this population shift are induced fit and conformational selection. In the induced‐fit mechanism, ligands bind to inactive receptor conformations prior to the conformational transition of the receptor. In the conformational‐selection mechanism, ligands bind to active conformations after the conformational transition. For the peptide‐activated neurotensin receptor 1, stopped‐flow mixing experiments that probe the chemical relaxation into binding equilibrium and conformational transition rates measured with NMR experiments indicate an induced‐fit mechanism. For the small‐molecule‐activated β2‐adrenergic receptor, an induced‐fit mechanism has been inferred from a decrease of ligand association rates after stabilization of the active receptor conformation. A structural explanation for the induced‐fit mechanism of the β2‐adrenergic receptor is a closed lid over the binding site that blocks ligand entry in the active conformation. Since constriction and closing of the ligand‐binding site in the active conformation is rather common for small‐molecule‐activated and peptide‐activated GPCRs, induced fit is likely shared as allosteric mechanism by these GPCRs.

Allosteric signaling of G‐protein‐coupled receptors (GPCRs) involves a population shift from inactive to active receptor conformations upon binding of ligand agonists. Kinetic and structural data indicate that this population shift is induced by ligand binding to inactive receptor conformations prior to the conformational change from inactive to active.

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