In silico analysis of the binding of agonists and blockers to the β2-adrenergic receptor.
In silico analysis of the binding of agonists and blockers to the β2-adrenergic receptor.
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激动剂和阻断剂与 β2-肾上腺素能受体结合的硅学分析。
DOI：
10.1016/j.jmgm.2011.01.005
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发表时间：
2011-04
影响因子：
2.9
通讯作者：
Costanzi, Stefano
中科院分区：
文献类型：
--
作者：
Vilar, Santiago;Karpiak, Joel;Berk, Barkin;Costanzi, Stefano
关键词：
G蛋白偶联受体（GPCR）的激活是一种复杂的现象。在这里，我们将诱导拟合对接（IFD）与线性判别分析（LDA）相结合，以生成关于激动剂结合诱导β2-肾上腺素能受体构象变化的假设，这是表征受体激活的事件序列的初步假设。这一分析得到了后续分子动力学研究的证实，表明激动剂诱导受体第五跨膜结构域（TM 5）的细微运动。此外，分子动力学还强调了TM 5和第二细胞外环（EL 2）的运动之间的相关性，这表明EL 2的运动自由度是激动剂诱导的TM 5位移所必需的。重要的是，我们还表明，IFD/LDA程序可以用作计算手段，以区分激动剂和阻断剂的基础上诱导的受体的差异构象变化。特别是，获得的两个最具预测性的模型是基于Ser 207诱导的RMSD和TM 5诱导的逆时针旋转。
Activation of G protein-coupled receptors (GPCRs) is a complex phenomenon. Here, we applied Induced Fit docking (IFD) in tandem with linear discriminant analysis (LDA) to generate hypotheses on the conformational changes induced to the β2-adrenergic receptor by agonist binding, preliminary to the sequence of events that characterize activation of the receptor. This analysis, corroborated by a follow-up molecular dynamics study, suggested that agonists induce subtle movements to the fifth transmembrane domain (TM5) of the receptor. Furthermore, molecular dynamics also highlighted a correlation between movements of TM5 and the second extracellular loop (EL2), suggesting that freedom of motion of EL2 is required for the agonist-induced TM5 displacement. Importantly, we also showed that the IFD/LDA procedure can be used as a computational means to distinguish agonists from blockers on the basis of the differential conformational changes induced to the receptor. In particular, the two most predictive models obtained are based on the RMSD induced to Ser207 and on the counterclockwise rotation induced to TM5.
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影响因子：
15
作者：
Bhattacharya, Supriyo;Vaidehi, Nagarajan
通讯作者：
Vaidehi, Nagarajan
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：
Shaw, David E.
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
4.8
作者：
Ballesteros, JA;Jensen, AD;Javitch, JA
通讯作者：
Javitch, JA
影响因子：
7.3
作者：
Costanzi, Stefano
通讯作者：
Costanzi, Stefano