Drug Binding Poses Relate Structure with Efficacy in the μ Opioid Receptor

Journal of Molecular Biology
Katy J SutcliffeRichard B Sessions

Abstract

The μ-opioid receptor (MOPr) is a clinically important G protein-coupled receptor that couples to Gi/o proteins and arrestins. At present, the receptor conformational changes that occur following agonist binding and activation are poorly understood. This study has employed molecular dynamics simulations to investigate the binding mode and receptor conformational changes induced by structurally similar opioid ligands of widely differing intrinsic agonist efficacy, norbuprenorphine, buprenorphine, and diprenorphine. Bioluminescence resonance energy transfer assays for Gi activation and arrestin-3 recruitment in human embryonic kidney 293 cells confirmed that norbuprenorphine is a high efficacy agonist, buprenorphine a low efficacy agonist, and diprenorphine an antagonist at the MOPr. Molecular dynamics simulations revealed that these ligands adopt distinct binding poses and engage different subsets of residues, despite sharing a common morphinan scaffold. Notably, norbuprenorphine interacted with sodium ion-coordinating residues W2936.48 and N1503.35, whilst buprenorphine and diprenorphine did not. Principal component analysis of the movements of the receptor transmembrane domains showed that the buprenorphine-bound receptor occu...Continue Reading

Citations

May 6, 2019·Journal of Molecular Modeling·Piotr F J LipińskiJoanna Sadlej
Sep 1, 2019·International Journal of Molecular Sciences·Ye ZouHo-Leung Ng
May 7, 2019·Current Medicinal Chemistry·Justyna Piekielna-CiesielskaAnna Janecka
Dec 7, 2018·Pain Management·Aliza T Ehrlich, Emmanuel Darcq
Oct 16, 2019·Proceedings of the National Academy of Sciences of the United States of America·Zoltan DekanMacDonald J Christie
Dec 6, 2019·Peptides·Richard J Bodnar
Jan 15, 2021·The Journal of Pharmacology and Experimental Therapeutics·D E SelleyS S Negus
Apr 6, 2021·Clinical Drug Investigation·Joao P De AquinoMehmet Sofuoglu
May 25, 2021·British Journal of Pharmacology·Eamonn KellyGraeme Henderson
Nov 16, 2021·Journal of Chemical Information and Modeling·Fuhui ZhangXuemei Pu

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Methods Mentioned

BETA
X-ray
bioluminescence resonance energy transfer
BRET
PCA
NMR
transfection

Software Mentioned

PathHunter
CHARMM
VMD
MD
aMD
GraphPad Prism
Chimera
cMD
- GUI
Antechamber

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