How μ-opioid receptor recognizes fentanyl

Vo, Quynh N.; Mahinthichaichan, Paween; Shen, Jana; Ellis, Christopher R.

doi:10.1038/s41467-021-21262-9

How μ-opioid receptor recognizes fentanyl

Journal Article · Fri Feb 12 00:00:00 EST 2021 · Nature Communications

DOI:https://doi.org/10.1038/s41467-021-21262-9· OSTI ID:1765423

; Mahinthichaichan, Paween; ;

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.

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Research Organization:: Oak Ridge Institute for Science and Education (ORISE), Oak Ridge, TN (United States)

Sponsoring Organization:: National Institutes of Health (NIH); USDOE; USDOE Office of Science (SC)

Grant/Contract Number:: SC0014664

OSTI ID:: 1765423

Alternate ID(s):: OSTI ID: 1816756

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 12; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United Kingdom

Language:: English

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