文献类型：期刊文献

中文题名：Computational insights into the G-protein-biased activation and inactivation mechanisms of the μ opioid receptor

英文题名：Computational insights into the G-protein-biased activation and inactivation mechanisms of the μ opioid receptor

作者：Jian-xin CHENG[1,2];Tao CHENG[1];Wei-hua LI[1];Gui-xia LIU[1];Wei-liang ZHU[2];Yun TANG[1]

机构：[1]Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China;[2]Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China

年份：2018

卷号：39

期号：1

起止页码：154

中文期刊名：Acta Pharmacologica Sinica

外文期刊名：中国药理学报（英文版）

收录：CSTPCD;;Scopus;CSCD:【CSCD2017_2018】；PubMed;

基金：This work was supported by the National Natural Science Foundation of China （Grants 81673356 and U1603122） and the 111 Project （Grant B07023）.

语种：英文

中文关键词：G-protein-coupled receptor; p opioid receptor; molecular dynamics; activation switch; G-protein bias;β-arrestin signaling;TRV130; BUT2; β-FNA; naltrexone

外文关键词：G-protein-coupled receptor; p opioid receptor; molecular dynamics; activation switch; G-protein bias;β-arrestin signaling;TRV130; BUT2; β-FNA; naltrexone

摘要：The p 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 p-OR agonists promise to be developed as analgesics. Thus, TRV130, the first representative/J-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/J-OR, we constructed five/J-OR systems that were in complexes with the G-protein-biased agonists TRV130 and BUT2, the antagonists/3-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 p-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/3-arrestin signaling, which in turn affected G-protein-biased activation of p-OR. TRV130 was found to stabilize W^6.48 by interacting with Y^743. In addition, we obtained useful information regarding p-OR-biased activation, such as strong stabilization of W7.35 through a hydrophobic ring interaction in the TRV130 system. These findings may facilitate understanding of μ-OR biased activation and the design of new biased ligands for GPCRs.
The p 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 p-OR agonists promise to be developed as analgesics. Thus, TRV130, the first representative/J-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/J-OR, we constructed five/J-OR systems that were in complexes with the G-protein-biased agonists TRV130 and BUT2, the antagonists/3-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 p-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/3-arrestin signaling, which in turn affected G-protein-biased activation of p-OR. TRV130 was found to stabilize W^6.48 by interacting with Y^743. In addition, we obtained useful information regarding p-OR-biased activation, such as strong stabilization of W7.35 through a hydrophobic ring interaction in the TRV130 system. These findings may facilitate understanding of μ-OR biased activation and the design of new biased ligands for GPCRs.