Journal
JOURNAL OF MOLECULAR BIOLOGY
Volume 429, Issue 12, Pages 1840-1851Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jmb.2017.05.009
Keywords
G protein-coupled receptor; mu-opioid receptor; molecular dynamics; buprenorphine
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Funding
- Biotechnology and Biological Sciences Research Council (BBSRC) [BB/J014400/1]
- Biotechnology and Biological Sciences Research Council [1653834] Funding Source: researchfish
- MRC [MR/J013269/1] Funding Source: UKRI
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The mu-opioid receptor (MOPr) is a clinically important G protein-coupled receptor that couples to G(i/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 G(i) 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 W293(6.48) and N150(3.35), whilst buprenorphine and diprenorphine did not. Principal component analysis of the movements of the receptor transmembrane domains showed that the buprenorphine-bound receptor occupied a distinct set of conformations to the norbuprenorphine-bound receptor. Addition of an allosteric sodium ion caused the receptor and ligand to adopt an inactive conformation. The differences in ligand residue interactions and receptor conformations observed here may underlie the differing efficacies for cellular signalling outputs for these ligands. (C) 2017 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
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