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

Authors: Jian-xin CHENG1,2, Tao CHENG1, Wei-hua LI1, Gui-xia LIU1, Wei-liang ZHU2, Yun TANG1
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
Corresponding to: Yun TANG:,
DOI: 10.1038/aps.2017.158
Received: 30 May 2017
Accepted: 1 August 2017
Advance online: 30 November 2017


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 W6.48 and Y7.43 (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 W6.48 by interacting with Y7.43. In addition, we obtained useful information regarding μ-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.
Keywords: G-protein-coupled receptor; μ opioid receptor; molecular dynamics; activation switch; G-protein bias; β-arrestin signaling; TRV130; BU72; β-FNA; naltrexone