Activation mechanism of theβ₂-adrenergic receptor

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. molecular dynamics | ligand | biased signaling | functional selectivity | beta-adrenergic

Activation of G-protein-coupled receptors correlates with the formation of a continuous internal water pathway

“…Noticeably, the VG of BIA/b 2 AR is comparable with VG of BIA/b 2 AR/G a , although no G a is present at cytoplasmic region in BIA/b 2 AR. This is in agreement with the previous finding 24 that b 2 AR requires tens of microseconds to reset back to inactive states from a fully activated structure. However, we still observed that VG of BIA/b 2 AR already shrunk to B700 Å 3 compared with fully activated BIA/b 2 AR/ G a ( Supplementary Fig.…”

Development and Characterization of Pepducins as Gs-biased Allosteric Agonists*

“…Plausibly, ICL3-9 may have the ability to modulate movement of TM5 and promote a unique active conformation utilizing the helical extension of TM5 to unconventionally activate G s . It should also be noted that molecular dynamics simulations of the ␤ 2 AR show a weak relationship between conformational changes in the ligand-binding pocket and TM5/6 movement (8,53). Thus, the ability of the pepducin to promote conformational changes in this region does not depend on operation through an orthosteric mechanism.…”

From G Protein-coupled Receptor Structure Resolution to Rational Drug Design

“…Using these approaches, it has been shown that there is a spectrum of conformations more complex than the simple active and inactive conformations. Specifically, computational approaches have provided evidence for metastable states that will be very difficult if not impossible to capture experimentally (32). Atomic-level simulations based on the available crystal structures of the ␤ 2 -adrenergic receptor reveal that different sections of the receptor (the ligand binding site, G protein binding site, and connector region) exhibit weak allosteric coupling and can occupy different conformations independently (32).…”

“…Specifically, computational approaches have provided evidence for metastable states that will be very difficult if not impossible to capture experimentally (32). Atomic-level simulations based on the available crystal structures of the ␤ 2 -adrenergic receptor reveal that different sections of the receptor (the ligand binding site, G protein binding site, and connector region) exhibit weak allosteric coupling and can occupy different conformations independently (32). The consequence of this loose structural relationship is that ligand efficacy only needs modulation of the equilibrium between different conformations to achieve distinct pharmacological outcomes.…”