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

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 <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:semantics><mml:msub><mml:mi>β</mml:mi> <mml:mn>2</mml:mn></mml:msub> <mml:annotation>$\ubeta_2$</mml:annotation></mml:semantics> </mml:math> -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 <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:semantics><mml:msub><mml:mi>β</mml:mi> <mml:mn>2</mml:mn></mml:msub> <mml:annotation>$\ubeta_2$</mml:annotation></mml:semantics> </mml:math> -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.