Activation mechanism of the<i>β</i>₂-adrenergic receptor

TLDR

A third of marketed drugs target G‑protein‑coupled receptors, yet crystal structures of these receptors do not reveal how they transition between active and inactive states. The study proposes an activation mechanism for the β2‑adrenergic receptor based on atomic‑level simulations showing an agonist‑bound receptor spontaneously shifting from the active to the inactive crystallographic conformation. The mechanism involves a loosely coupled allosteric network of three regions that can each adopt multiple conformations, linking extracellular drug‑binding perturbations to large intracellular G‑protein‑binding site changes. Simulations identified an intermediate that may bind G protein during activation and indicate that the earliest structural changes occur intracellularly, far from the drug‑binding site, providing a foundation for designing drugs that stabilize specific receptor conformations.

Abstract

A third of marketed drugs act by binding to a G-protein-coupled receptor (GPCR) and either triggering or preventing receptor activation. Although recent crystal structures have provided snapshots of both active and inactive functional states of GPCRs, these structures do not reveal the mechanism by which GPCRs transition between these states. Here we propose an activation mechanism for the β 2 -adrenergic receptor, a prototypical GPCR, based on atomic-level simulations in which an agonist-bound receptor transitions spontaneously from the active to the inactive crystallographically observed conformation. A loosely coupled allosteric network, comprising three regions that can each switch individually between multiple distinct conformations, links small perturbations at the extracellular drug-binding site to large conformational changes at the intracellular G-protein-binding site. Our simulations also exhibit an intermediate that may represent a receptor conformation to which a G protein binds during activation, and suggest that the first structural changes during receptor activation often take place on the intracellular side of the receptor, far from the drug-binding site. By capturing this fundamental signaling process in atomic detail, our results may provide a foundation for the design of drugs that control receptor signaling more precisely by stabilizing specific receptor conformations.