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Conformational dynamics of the μ-opioid receptor determine ligand intrinsic efficacy. | LitMetric

Conformational dynamics of the μ-opioid receptor determine ligand intrinsic efficacy.

bioRxiv

Beijing Advanced Innovation Center for Structural Biology, Beijing Frontier Research Center for Biological Structure, School of Life Sciences, Tsinghua University; Beijing, 100084, China.

Published: April 2023

AI Article Synopsis

Article Abstract

The μ-opioid receptor (μOR) is an important target for pain management and the molecular understanding of drug action will facilitate the development of better therapeutics. Here we show, using double electron-electron resonance (DEER) and single-molecule fluorescence resonance energy transfer (smFRET), how ligand-specific conformational changes of the μOR translate into a broad range of intrinsic efficacies at the transducer level. We identify several cytoplasmic receptor conformations interconverting on different timescales, including a pre-activated receptor conformation which is capable of G protein binding, and a fully activated conformation which dramatically lowers 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 protein G.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10168371PMC
http://dx.doi.org/10.1101/2023.04.28.538657DOI Listing

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