Structural and dynamic insights into the activation of the μ-opioid receptor by an allosteric modulator

Shun Kaneko, Shunsuke Imai (), Tomomi Uchikubo-Kamo, Tamao Hisano, Nobuaki Asao, Mikako Shirouzu and Ichio Shimada ()
Additional contact information
Shun Kaneko: Center for Biosystems Dynamics Research (BDR)
Shunsuke Imai: Center for Biosystems Dynamics Research (BDR)
Tomomi Uchikubo-Kamo: Center for Biosystems Dynamics Research (BDR)
Tamao Hisano: Center for Biosystems Dynamics Research (BDR)
Nobuaki Asao: Center for Biosystems Dynamics Research (BDR)
Mikako Shirouzu: Center for Biosystems Dynamics Research (BDR)
Ichio Shimada: Center for Biosystems Dynamics Research (BDR)

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: Abstract G-protein-coupled receptors (GPCRs) play pivotal roles in various physiological processes. These receptors are activated to different extents by diverse orthosteric ligands and allosteric modulators. However, the mechanisms underlying these variations in signaling activity by allosteric modulators remain largely elusive. Here, we determine the three-dimensional structure of the μ-opioid receptor (MOR), a class A GPCR, in complex with the Gi protein and an allosteric modulator, BMS-986122, using cryogenic electron microscopy. Our results reveal that BMS-986122 binding induces changes in the map densities corresponding to R1673.50 and Y2545.58, key residues in the structural motifs conserved among class A GPCRs. Nuclear magnetic resonance analyses of MOR in the absence of the Gi protein reveal that BMS-986122 binding enhances the formation of the interaction between R1673.50 and Y2545.58, thus stabilizing the fully-activated conformation, where the intracellular half of TM6 is outward-shifted to allow for interaction with the Gi protein. These findings illuminate that allosteric modulators like BMS-986122 can potentiate receptor activation through alterations in the conformational dynamics in the core region of GPCRs. Together, our results demonstrate the regulatory mechanisms of GPCRs, providing insights into the rational development of therapeutics targeting GPCRs.

Date: 2024
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-024-47792-6 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-47792-6

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-024-47792-6

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().