Abstract
SummaryMembranes are known to have modulatory effects on G protein-coupled receptors (GPCRs) via specific lipid interactions. However, the mechanisms of such modulations in physiological conditions and how they influence GPCR functions remain unclear. Here we report coarse-grained molecular dynamics simulations on the Adenosine A2a receptor in different conformational states embedded in an in vivo-mimetic membrane model. Nine lipid interaction sites were revealed. The strength of lipid interactions with these sites showed a degree of dependence on the conformational states of the receptor, suggesting that these lipids may regulate the conformational dynamics of the receptor. In particular, we revealed a dual role of PIP2 on A2aR activation that involves both stabilization of the characteristic outward tilt of TM6 and enhancement of A2aR-mini-Gs association. Our results demonstrated that the bound lipids allosterically regulate the functional properties of GPCRs. These protein-lipid interactions provide a springboard for design of allosteric modulators of GPCRs.
Highlights
The G protein-coupled receptors (GPCRs) form the largest superfamily in the mammalian genome
The sharp contrast between the relatively conserved orthosteric binding pockets and the wide spectrum of signals that GPCRs are able to elicit has resulted in a search for allosteric modulators that could fine-tune the conformational dynamics of the receptors
We focus on the Adenosine A2a receptor, a prototypical GPCR that plays a major role in the central nervous system in response to adenosine, as its structure has been determined in both an inactive (Jaakola et al, 2008) and active (Carpenter et al, 2016) state
Summary
The G protein-coupled receptors (GPCRs) form the largest superfamily in the mammalian genome. They bind to a wide range of ligands and convert extracellular signals to intracellular responses via interactions with either G proteins or b-arrestins (Zhou et al, 2017). Owing to their involvement in many physiological processes, GPCRs are targeted by about 30% of current drugs. Several recent structures have revealed allosteric binding sites on the extra-helical surface of GPCRs (Jazayeri et al, 2016; Song et al, 2017; Zhang et al, 2015), emphasizing the potential for modulation from outside of the helix bundles
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