Computational Mapping of the Conformational Transitions in Agonist Selective Pathways of a G-Protein Coupled Receptor
Computational Mapping of the Conformational Transitions in Agonist Selective Pathways of a G-Protein Coupled Receptor
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DOI：
10.1021/ja910700y
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发表时间：
2010-04-14
影响因子：
15
通讯作者：
Vaidehi, Nagarajan
中科院分区：
文献类型：
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作者：
Bhattacharya, Supriyo;Vaidehi, Nagarajan
G蛋白偶联受体（GPCR）的活性状态构象受结合配体的化学结构和功效的影响。深入了解活性状态的构象以及不同功效的配体的活化途径对于设计GPCR的功能特异性药物至关重要。从β 2-肾上腺素能受体的晶体结构开始，我们使用粗粒计算方法来理解两种完全激动剂、两种部分激动剂和一种反向激动剂对受体势能景观的调制。我们的粗粒方法包括一个系统的受体跨膜螺旋的构象跨越，然后在每个采样的构象能量最小化和配体redocking。我们已经推导出几种激动剂和部分激动剂的激活途径，使用Monte Carlo算法，这些都与荧光光谱测量。完全激动剂的计算途径开始于导致稳定中间体的能量下降步骤，随后是导致活性状态的势垒跨越。我们发现，屏障跨越涉及打破螺旋5和螺旋6之间的螺旋间氢键，和水的结合位点残基的极化促进屏障跨越。部分激动剂沙丁胺醇诱导的活化中的上坡步骤不同于完全激动剂去甲肾上腺素，并且源自螺旋6上的芳香残基的空间位阻。与沙丁胺醇稳定的构象虚拟配体筛选显示富集的非儿茶酚激动剂的去甲肾上腺素稳定的构象。我们的计算方法提供了一个前所未有的机会来推导实验假设，并了解GPCR的激活机制。
The active state conformation of a G-protein coupled receptor (GPCR) is influenced by the chemical structure and the efficacy of the bound ligand. Insight into the active state conformation as well as the activation pathway for ligands with different efficacies is critical in designing functionally specific drugs for GPCRs. Starting from the crystal structure of the beta 2-adrenergic receptor, we have used coarse grain computational methods to understand the modulation of the potential energy landscape of the receptor by two full agonists, two partial agonists, and an inverse agonist. Our coarse grain method involves a systematic conformational spanning of the receptor transmembrane helices followed by an energy minimization and ligand redocking in each sampled conformation. We have derived the activation pathways for several agonists and partial agonists, using a Monte Carlo algorithm, and these are in agreement with fluorescence spectroscopy measurements. The calculated pathways for the full agonists start with an energy downhill step leading to a stable intermediate followed by a barrier crossing leading to the active state. We find that the barrier crossing involves breaking of an interhelical hydrogen bond between helix5 and helix6, and polarization of the binding site residues by water facilitates the barrier crossing. The uphill step in the partial agonist salbutamol induced activation is distinct from full agonist norepinephrine, and originates from steric hindrance with the aromatic residues on helix6. Virtual ligand screening with the salbutamol-stabilized conformation shows enrichment of noncatechol agonists over the norepinephrine-stabilized conformation. Our computational method provides an unprecedented opportunity to derive hypotheses for experiments and also understand activation mechanisms in GPCRs.