Computational insights into the G-protein-biased activation and inactivation mechanisms of the μ opioid receptor
Computational insights into the G-protein-biased activation and inactivation mechanisms of the μ opioid receptor
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mu 阿片受体 G 蛋白偏向激活和失活机制的计算见解
DOI：
10.1038/aps.2017.158
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发表时间：
2018-01-01
影响因子：
8.2
通讯作者：
Tang, Yun
中科院分区：
文献类型：
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作者：
Cheng, Jian-xin;Cheng, Tao;Tang, Yun
μ阿片受体（OR）是G蛋白偶联受体（GPCR）的A类亚家族的成员，是治疗疼痛的主要靶标。G蛋白偏向的mu-OR激动剂有望被开发为镇痛剂。因此，第一个具有G蛋白偏倚的代表性mu-OR配体TRV 130已进入III期临床试验。为了鉴定mu-OR的详细的G蛋白偏向性激活和失活机制，我们构建了五个mu-OR系统，它们与G蛋白偏向性激动剂TRV 130和BU 72、拮抗剂β-FNA和纳洛酮以及游离受体复合。我们进行了一系列常规的分子动力学模拟和分析的G蛋白偏置的激活和失活机制的mu-OR。我们的研究结果，连同先前报道的突变结果，揭示了由残基W-6.48和Y-7.43（Ballesteros/Weinstein编号）组成的激活开关的操作模式，其活性分别负责β-arrestin信号传导的下调和上调，这反过来又影响G蛋白偏置的mu-OR激活。发现TRV 130通过与Y-7.43相互作用来稳定W-6.48。此外，我们还获得了关于μ-OR偏置激活的有用信息，例如TRV 130系统中通过疏水环相互作用对W-7.35的强稳定性。这些发现可能有助于理解mu-OR偏置激活和设计新的GPCR偏置配体。
The mu opioid receptor (OR), a member of the class A subfamily of G-protein coupled receptors (GPCRs), is a major target for the treatment of pain. G-protein biased mu-OR agonists promise to be developed as analgesics. Thus, TRV130, the first representative mu-OR ligand with G-protein bias, has entered into phase III clinical trials. To identify the detailed G-protein-biased activation and inactivation mechanisms of the mu-OR, we constructed five mu-OR systems that were in complexes with the G-protein-biased agonists TRV130 and BU72, the antagonists beta-FNA and naltrexone, as well as the free receptor. We performed a series of conventional molecular dynamics simulations and analyses of G-protein-biased activation and inactivation mechanisms of mu-OR. Our results, together with previously reported mutation results, revealed the operating mode of the activation switch composed of residues W-6.48 and Y-7.43 (Ballesteros/Weinstein numbering), the activity of which was responsible for down-and up-regulation, respectively, of the beta-arrestin signaling, which in turn affected G-protein-biased activation of mu-OR. TRV130 was found to stabilize W-6.48 by interacting with Y-7.43. In addition, we obtained useful information regarding mu-OR-biased activation, such as strong stabilization of W-7.35 through a hydrophobic ring interaction in the TRV130 system. These findings may facilitate understanding of mu-OR biased activation and the design of new biased ligands for GPCRs.