Activation mechanism of theβ2-adrenergic receptor

• DOI: 10.1073/pnas.1110499108
• Publication Date: 2011-10-27T01:12:07Z
• Authors: Ron O. Dror; Daniel H. Arlow; Paul Maragakis; Thomas J. Mildorf; Albert C. Pan; Huafeng Xu; David W. Borhani; David E. Shaw
• Keywords: Structural Biology; Conformational change

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