期刊
STRUCTURE
卷 27, 期 2, 页码 392-+出版社
CELL PRESS
DOI: 10.1016/j.str.2018.10.024
关键词
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资金
- Wellcome [208361/Z/17/Z]
- BBSRC [BB/R00126X/1]
- PRACE (Partnership for Advanced Computing in Europe) [2016163984]
- ERC [641317]
- MRC Program Grant [G1000819]
- Wellcome Trust Investigator Award [104633/Z/14/Z]
- Newton International Fellowship
- EPSRC [EP/L000253/1]
- BBSRC [BB/R00126X/1] Funding Source: UKRI
- EPSRC [EP/L000253/1, EP/R029407/1, EP/J010421/1] Funding Source: UKRI
- MRC [G1000819, MR/N020413/1] Funding Source: UKRI
Membranes 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.
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