Ligand efficacy modulates conformational dynamics of the μ-opioid receptor

• 成果类型: Article
• 署名作者: Zhao, Jiawei; Elgeti, Matthias; O'Brien, Evan S.; Sar, Cecilia P.; El Daibani, Amal; Heng, Jie; Sun, Xiaoou; White, Elizabeth; Che, Tao; Hubbell, Wayne L.; Kobilka, Brian K.; Chen, Chunlai
• 署名单位: Tsinghua University; Tsinghua University; Tsinghua University; University of California System; University of California Los Angeles; University of California System; University of California Los Angeles; Leipzig University; Stanford University; University of Pecs; Washington University (WUSTL)
• 刊物名称: Nature
• ISSN/ISSBN: 0028-5934
• DOI: 10.1038/s41586-024-07295-2
• 发表日期: 2024-05-09
• 关键词: structural insights; crystal-structure; activation; identification; analgesics; mechanism; cleavage

摘要

The mu-opioid receptor (mu OR) is an important target for pain management 1 and molecular understanding of drug action on mu OR will facilitate the development of better therapeutics. Here we show, using double electron-electron resonance and single-molecule fluorescence resonance energy transfer, how ligand-specific conformational changes of mu OR translate into a broad range of intrinsic efficacies at the transducer level. We identify several conformations of the cytoplasmic face of the receptor that interconvert on different timescales, including a pre-activated conformation that is capable of G-protein binding, and a fully activated conformation that markedly reduces GDP affinity within the ternary complex. Interaction of beta-arrestin-1 with the mu OR core binding site appears less specific and occurs with much lower affinity than binding of Gi. Studies on the mu-opioid receptor using fluorescent labelling of intracellular residues and energy transfer experiments in the presence of different ligands with or without G-protein binding reveals conformational changes that correlate to ligand efficacy.