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Title: How μ-opioid receptor recognizes fentanyl

Abstract

Abstract Roughly half of the drug overdose-related deaths in the United States are related to synthetic opioids represented by fentanyl which is a potent agonist of mu-opioid receptor (mOR). In recent years, X-ray crystal structures of mOR in complex with morphine derivatives have been determined; however, structural basis of mOR activation by fentanyl-like opioids remains lacking. Exploiting the X-ray structure of BU72-bound mOR and several molecular simulation techniques, we elucidated the detailed binding mechanism of fentanyl. Surprisingly, in addition to the salt-bridge binding mode common to morphinan opiates, fentanyl can move deeper and form a stable hydrogen bond with the conserved His297 6.52 , which has been suggested to modulate mOR’s ligand affinity and pH dependence by previous mutagenesis experiments. Intriguingly, this secondary binding mode is only accessible when His297 6.52 adopts a neutral HID tautomer. Alternative binding modes may represent a general mechanism in G protein-coupled receptor-ligand recognition.

Authors:
ORCiD logo; ; ORCiD logo; ORCiD logo
Publication Date:
Research Org.:
Oak Ridge Inst. for Science and Education (ORISE), Oak Ridge, TN (United States)
Sponsoring Org.:
USDOE Office of Science (SC); National Institutes of Health (NIH)
OSTI Identifier:
1765423
Alternate Identifier(s):
OSTI ID: 1816756
Grant/Contract Number:  
SC0014664; GM098818
Resource Type:
Published Article
Journal Name:
Nature Communications
Additional Journal Information:
Journal Name: Nature Communications Journal Volume: 12 Journal Issue: 1; Journal ID: ISSN 2041-1723
Publisher:
Nature Publishing Group
Country of Publication:
United Kingdom
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; biophysical models

Citation Formats

Vo, Quynh N., Mahinthichaichan, Paween, Shen, Jana, and Ellis, Christopher R. How μ-opioid receptor recognizes fentanyl. United Kingdom: N. p., 2021. Web. doi:10.1038/s41467-021-21262-9.
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Vo, Quynh N., Mahinthichaichan, Paween, Shen, Jana, & Ellis, Christopher R. How μ-opioid receptor recognizes fentanyl. United Kingdom. https://doi.org/10.1038/s41467-021-21262-9
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Vo, Quynh N., Mahinthichaichan, Paween, Shen, Jana, and Ellis, Christopher R. Fri . "How μ-opioid receptor recognizes fentanyl". United Kingdom. https://doi.org/10.1038/s41467-021-21262-9.
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@article{osti_1765423,
title = {How μ-opioid receptor recognizes fentanyl},
author = {Vo, Quynh N. and Mahinthichaichan, Paween and Shen, Jana and Ellis, Christopher R.},
abstractNote = {Abstract Roughly half of the drug overdose-related deaths in the United States are related to synthetic opioids represented by fentanyl which is a potent agonist of mu-opioid receptor (mOR). In recent years, X-ray crystal structures of mOR in complex with morphine derivatives have been determined; however, structural basis of mOR activation by fentanyl-like opioids remains lacking. Exploiting the X-ray structure of BU72-bound mOR and several molecular simulation techniques, we elucidated the detailed binding mechanism of fentanyl. Surprisingly, in addition to the salt-bridge binding mode common to morphinan opiates, fentanyl can move deeper and form a stable hydrogen bond with the conserved His297 6.52 , which has been suggested to modulate mOR’s ligand affinity and pH dependence by previous mutagenesis experiments. Intriguingly, this secondary binding mode is only accessible when His297 6.52 adopts a neutral HID tautomer. Alternative binding modes may represent a general mechanism in G protein-coupled receptor-ligand recognition.},
doi = {10.1038/s41467-021-21262-9},
journal = {Nature Communications},
number = 1,
volume = 12,
place = {United Kingdom},
year = {Fri Feb 12 00:00:00 EST 2021},
month = {Fri Feb 12 00:00:00 EST 2021}
}
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https://doi.org/10.1038/s41467-021-21262-9
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