computationalinsightsintothegproteinbiasedactivationandinactivationmechanismsoftheopioidreceptor

doi:10.1038/aps.2017.158

	computationalinsightsintothegproteinbiasedactivationandinactivationmechanismsoftheopioidreceptor
	Cheng Jianxin 1; Cheng Tao 1; Li Weihua 1; Liu Guixia 1; Zhu Weiliang 2; Tang Yun 1
刊名	actapharmacologicasinica
	2018
卷号	39 期号:1 页码:154
关键词	G-protein-coupled receptor μ opioid receptor molecular dynamics activation switch G-protein bias β-arrestin signaling TRV130 BU72 β-FNA naltrexone
ISSN号	1671-4083
DOI	10.1038/aps.2017.158
英文摘要	The μ 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 μ-OR agonists promise to be developed as analgesics. Thus, TRV130, the first representative μ-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 μ-OR,we constructed five μ-OR systems that were in complexes with the G-protein-biased agonists TRV130 and BU72,the antagonists β-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 μ-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 β-arrestin signaling, which in turn affected G-protein-biased activation of μ-OR. TRV130 was found to stabilize W~(6.48) by interacting with Y~(7.43). In addition, we obtained useful information regarding μ-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 μ-OR biased activation and the design of new biased ligands for GPCRs.
语种	英语
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/283032]
专题	中国科学院上海药物研究所
作者单位	1.华东理工大学 2.中国科学院上海药物研究所
推荐引用方式 GB/T 7714	Cheng Jianxin,Cheng Tao,Li Weihua,et al. computationalinsightsintothegproteinbiasedactivationandinactivationmechanismsoftheopioidreceptor[J]. actapharmacologicasinica,2018,39(1):154.
APA	Cheng Jianxin,Cheng Tao,Li Weihua,Liu Guixia,Zhu Weiliang,&Tang Yun.(2018).computationalinsightsintothegproteinbiasedactivationandinactivationmechanismsoftheopioidreceptor.actapharmacologicasinica,39(1),154.
MLA	Cheng Jianxin,et al."computationalinsightsintothegproteinbiasedactivationandinactivationmechanismsoftheopioidreceptor".actapharmacologicasinica 39.1(2018):154.