@article{APS9713,
author = {Jian-xin CHENG and Tao CHENG and Wei-hua LI and Gui-xia LIU and Wei-liang ZHU and Yun TANG},
title = {Computational insights into the G-protein-biased activation and inactivation mechanisms of the μ opioid receptor},
journal = {Acta Pharmacologica Sinica},
volume = {39},
number = {1},
year = {2017},
keywords = {},
abstract = {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 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.},
issn = {1745-7254}, url = {http://www.chinaphar.com/article/view/9713}
}