Abstract
Understanding the mechanisms of signaling proteins such as G-protein-coupled receptors (GPCRs) requires definition of their conformational states and the pathways connecting those states. The recent crystal structures of the beta-2 and beta-1 adrenergic receptors in a presumably inactive state constituted a major advance toward this goal, but also raised new questions. Although earlier biochemical observations had suggested that the beta adrenergic receptors possessed a set of contacts between helices 3 and 6, known as the ionic lock, which was believed to form a molecular switch for receptor activation, the crystal structures lacked these contacts. The unexpectedly broken ionic lock has provoked a great deal of speculation, raising questions about whether the structures accurately represent the inactive receptor state and whether the ionic lock plays a role in activation of these and other GPCRs. To address these questions, we performed microsecond-timescale molecular dynamics simulations of the beta-2 adrenergic receptor in multiple wild-type and mutant forms. Our observations of the behavior of the ionic lock, along with the formation of several novel structural elements in the extramembrane loops during our simulations, paint a more complete picture of the inactive state of the beta adrenergic receptors, reconciling the crystal structures with biochemical studies.
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