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Computational insights into the G-protein-biased activation and inactivation mechanisms of the mu opioid receptor

文献类型：期刊论文

作者Cheng, Jian-xin1,2; Cheng, Tao1; Li, Wei-hua1; Liu, Gui-xia1; Zhu, Wei-liang2; Tang, Yun1
刊名ACTA PHARMACOLOGICA SINICA
出版日期2018-01
卷号39期号:1页码:154-164
关键词G-protein-coupled receptor mu opioid receptor molecular dynamics activation switch G-protein bias beta-arrestin signaling TRV130 BU72 beta-FNA naltrexone
ISSN号1671-4083
DOI10.1038/aps.2017.158
文献子类Article
英文摘要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.
WOS关键词GENERAL FORCE-FIELD ; COUPLED RECEPTORS ; NPXXY(X)(5,6)F MOTIF ; MOLECULAR SWITCHES ; ACCURATE DOCKING ; LIGAND ; BETA-ARRESTIN-2 ; DISCOVERY ; RHODOPSIN ; MORPHINE
资助项目National Natural Science Foundation of China[81673356] ; National Natural Science Foundation of China[U1603122] ; 111 Project[B07023]
WOS研究方向Chemistry ; Pharmacology & Pharmacy
语种英语
CSCD记录号CSCD:6159151
WOS记录号WOS:000423867300015
出版者ACTA PHARMACOLOGICA SINICA
源URL[http://119.78.100.183/handle/2S10ELR8/272339]  
专题药物发现与设计中心
通讯作者Tang, Yun
作者单位1.East China Univ Sci & Technol, Shanghai Key Lab New Drug Design, Sch Pharm, Shanghai 200237, Peoples R China;
2.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Cheng, Jian-xin,Cheng, Tao,Li, Wei-hua,et al. Computational insights into the G-protein-biased activation and inactivation mechanisms of the mu opioid receptor[J]. ACTA PHARMACOLOGICA SINICA,2018,39(1):154-164.
APA Cheng, Jian-xin,Cheng, Tao,Li, Wei-hua,Liu, Gui-xia,Zhu, Wei-liang,&Tang, Yun.(2018).Computational insights into the G-protein-biased activation and inactivation mechanisms of the mu opioid receptor.ACTA PHARMACOLOGICA SINICA,39(1),154-164.
MLA Cheng, Jian-xin,et al."Computational insights into the G-protein-biased activation and inactivation mechanisms of the mu opioid receptor".ACTA PHARMACOLOGICA SINICA 39.1(2018):154-164.

入库方式： OAI收割

来源：上海药物研究所

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