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Structural insights into positive and negative allosteric regulation of a G protein-coupled receptor through protein-lipid interactions.

ABSTRACT: Lipids are becoming known as essential allosteric modulators of G protein-coupled receptor (GPCRs). However, how they exert their effects on GPCR conformation at the atomic level is still unclear. In light of recent experimental data, we have performed several long-timescale molecular dynamics (MD) simulations, totalling 24 ?s, to rigorously map allosteric modulation and conformational changes in the ?2 adrenergic receptor (?2AR) that occur as a result of interactions with three different phospholipids. In particular, we identify different sequential mechanisms behind receptor activation and deactivation, respectively, mediated by specific lipid interactions with key receptor regions. We show that net negatively charged lipids stabilize an active-like state of ?2AR that is able to dock Gs? protein. Clustering of anionic lipids around the receptor with local distortion of membrane thickness is also apparent. On the other hand, net-neutral zwitterionic lipids inactivate the receptor, generating either fully inactive or intermediate states, with kinetics depending on lipid headgroup charge distribution and hydrophobicity. These chemical differences alter membrane thickness and density, which differentially destabilize the ?2AR active state through lateral compression effects.

SUBMITTER: Bruzzese A

PROVIDER: S-EPMC5849739 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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