Ligand efficacy modulates conformational dynamics of the µ-opioid receptor
Jiawei Zhao, Matthias Elgeti, Evan S. O’Brien, Cecı́lia P. Sár, Amal EI Daibani, Jie Heng, Xiaoou Sun, Elizabeth White, Tao Che, Wayne L. Hubbell, Brian K. Kobilka, Chunlai Chen
Abstract
Abstract The µ-opioid receptor (µOR) is an important target for pain management 1 and molecular understanding of drug action on µOR 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 µOR 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 β-arrestin-1 with the μOR core binding site appears less specific and occurs with much lower affinity than binding of G i .