Ligand efficacy modulates conformational dynamics of the µ-opioid receptor.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 38600384.
- Also identified by DOI 10.1038/s41586-024-07295-2 and PMC identifier 11078757.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
The µ-opioid receptor (µOR) is an important target for pain management<sup>1</sup> 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<sub>i</sub>.
Medical subject headings
- Ligands
- Protein Conformation
- Receptors, Opioid, mu