TY - JOUR AU - CHENG Jian-xin AU - CHENG Tao AU - LI Wei-hua AU - LIU Gui-xia AU - ZHU Wei-liang AU - TANG Yun PY - 2017 TI - Computational insights into the G-protein-biased activation and inactivation mechanisms of the μ opioid receptor JF - Acta Pharmacologica Sinica; Vol 39, No 1 (January 2018): Acta Pharmacologica Sinica Y2 - 2017 KW - N2 - Abstract 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. UR - http://www.chinaphar.com/article/view/9713