Work

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

Year: 2025

Type: review

Abstract: 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 ‐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 ‐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.

Source: BioEssays

DOI: 10.1002/bies.70082

Authors: Kazem Asadollahi, Paul R. Gooley, Thomas R. Weikl

Institutions: The University of Melbourne, Max Planck Institute of Colloids and Interfaces

Language: English

Topic: Receptor Mechanisms and Signaling

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $5,330