Activation mechanism of the β2-adrenergic receptor.
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.
DE Shaw Research, New York, NY 10036, USA. Ron.Dror@DEShawResearch.com
Ron O
RO
Dror
Daniel H
DH
Arlow
Paul
P
Maragakis
Thomas J
TJ
Mildorf
Albert C
AC
Pan
Huafeng
H
Xu
David W
DW
Borhani
David E
DE
Shaw
D000495:Allosteric Site; D020816:Amino Acid Motifs; D001665:Binding Sites; D020134:Catalytic Domain; D003198:Computer Simulation; D018360:Crystallography, X-Ray / Q000379:methods; D019204:GTP-Binding Proteins / Q000737:chemistry; D006801:Humans; D008024:Ligands; D008954:Models, Biological; D008968:Molecular Conformation; D011487:Protein Conformation; D011522:Protons; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*; D015398:Signal Transduction; D014443:Tyrosine / Q000737:chemistry
D008024:Ligands; D011522:Protons; D018343:Receptors, Adrenergic, beta-2; D014443:Tyrosine; D019204:GTP-Binding Proteins