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

• 来源期刊: 中国药理学报（英文版）
• 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
• 年，卷（期）: 2018,（1）
• 页码范围: 154-164
• 页数: 11页
• 语种: 英文
• DOI: 10.1038/aps.2017.158

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,TRY130,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 inactivationmechanisms of the μ-OR,we constructed five μ-OR systems that were in complexes with the G-protein-biased agonists TRV130 and BU72,the antagonistsβ-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 theβ-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.