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.
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Acknowledgements
All simulations were performed on the high-performance computing cluster kindly provided by Prof Bang-ce YE of the State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology. This work was supported by the National Natural Science Foundation of China (Grants 81673356 and U1603122) and the 111 Project (Grant B07023).
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Cheng, Jx., Cheng, T., Li, Wh. et al. Computational insights into the G-protein-biased activation and inactivation mechanisms of the μ opioid receptor. Acta Pharmacol Sin 39, 154–164 (2018). https://doi.org/10.1038/aps.2017.158
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DOI: https://doi.org/10.1038/aps.2017.158
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