Structural insights into positive and negative allosteric regulation of a G protein-coupled receptor through protein-lipid interactions.
Structural insights into positive and negative allosteric regulation of a G protein-coupled receptor through protein-lipid interactions.
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DOI：
10.1038/s41598-018-22735-6
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发表时间：
2018-03-13
影响因子：
4.6
通讯作者：
Giraldo J
中科院分区：
文献类型：
--
作者：
Bruzzese A;Gil C;Dalton JAR;Giraldo J
脂质被认为是G蛋白偶联受体（GPCRs）的重要变构调节剂。然而，它们如何在原子水平上对GPCR构象发挥作用仍不清楚。根据最近的实验数据，我们进行了几次长时间尺度的分子动力学（MD）模拟，总计24 μs，以严格映射β2肾上腺素能受体（β2AR）与三种不同磷脂相互作用的变构调节和构象变化。特别是，我们确定不同的顺序机制背后的受体激活和失活，分别介导的特定脂质与关键受体区域的相互作用。我们发现，净负电荷脂质稳定了β2AR的活性样状态，能够对接Gsα蛋白。受体周围的阴离子脂质聚集，膜厚度局部变形也很明显。另一方面，净中性两性离子脂质与受体结合，产生完全无活性或中间状态，动力学取决于脂质头基电荷分布和疏水性。这些化学差异改变了膜的厚度和密度，通过侧向压缩效应使β2AR活性状态不稳定。
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 μs, to rigorously map allosteric modulation and conformational changes in the β2 adrenergic receptor (β2AR) 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 β2AR that is able to dock Gsα 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 β2AR active state through lateral compression effects.
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DOI：
10.1073/pnas.0811065106
发表时间：
2009-03-24
影响因子：
11.1
作者：
Dror, Ron O.;Arlow, Daniel H.;Shaw, David E.
通讯作者：
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影响因子：
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影响因子：
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DOI：
10.1073/pnas.1110499108
发表时间：
2011-11-15
影响因子：
11.1
作者：
Dror, Ron O.;Arlow, Daniel H.;Shaw, David E.
通讯作者：
Shaw, David E.
影响因子：
14.9
作者：
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