Author Correction: Structural insights into μ-opioid receptor activation

Huang, Weijiao; Manglik, Aashish; Venkatakrishnan, AJ; Laeremans, Toon; Feinberg, Evan N.; Sanborn, Adrian L.; Kato, Hideaki; Livingston, Kathryn E.; Thorsen, Thor Seneca; Kling, Ralf C.; Granier, Sébastien; Gmeiner, Peter; Husbands, Stephen M.; Traynor, John R.; Weis, William I.; Steyaert, Jan; Dror, Ron O.; Kobilka, Brian K.

doi:10.1038/s41586-020-2542-z

Cited by 45 publications

(78 citation statements)

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“…9,11,29,30 Previous experiments 30 and simulations 9,11,29 demonstrated that Asp114 binds a sodium ion in the inactive but not active state of GPCRs. Based on the lack of sodium binding, two previous MD studies used a protonated Asp114 9,11 , while other published work did not specify the protonation state 18,31,32 . The CpHMD titration gave a pK a of 4.8 ± 0.30 for the apo and 5.1 ± 0.26/0.29 for the fentanylbound mOR in the D147-or H297-binding mode.…”

Section: Resultsmentioning

confidence: 99%

“…In the first WE simulation of 24 μs aggregate time, His297 was fixed in the HIE tautomer (Nϵ atom of imidazole is protonated), as in the recent mOR simulations by the Dror group 9,11 . The WE-HIE simulation proceeded as expected.…”

Section: Resultsmentioning

confidence: 99%

“…Fentanyl and morphine opioids produce strong analgesic responses through binding and subsequent activation of a class A G protein-coupled receptor (GPCR) μ-opioid receptor (mOR) 8 . In recent years, high-resolution crystal structures of mOR in complex with the morphinan agonist BU72 9 , antagonist β-FNA 10 , as well as the endogenous peptide analog agonist DAMGO 11 have been determined, featuring a salt bridge between a charged amine group of the ligand and a conserved residue Asp147 on the transmembrane helix (TM) 3 (Asp 3.32 in the Ballesteros-Weinstein numbering 12 ) of mOR ( Fig. 1a).…”

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confidence: 99%

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How μ-opioid receptor recognizes fentanyl

et al. 2021

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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 His2976.52, 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 His2976.52 adopts a neutral HID tautomer. Alternative binding modes may represent a general mechanism in G protein-coupled receptor-ligand recognition.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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confidence: 99%

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How μ-opioid receptor recognizes fentanyl

et al. 2021

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“…We utilized the active-state agonist-bound MOP receptor X-ray crystal structure (PDB ID: 5C1M) published in late 2015 to develop an in silico homology model of the KOP receptor in its active state (Huang et al, 2015; Vardy et al, 2013). The full sequence of human KOP receptor was downloaded from the Uniprot website (http://www.uniprot.org/uniprot/P41145) and used to define key residue differences between KOP and MOP receptors.…”

Section: Computational Modelingmentioning

confidence: 99%

“…The full sequence of human KOP receptor was downloaded from the UniProt website (http://www.uniprot.org/uniprot/P41145) and used to define key residue differences between KOP and MOP receptors. We utilized chain A of the 5C1M crystal structure, in which the MOP receptor is bound to the morphinan agonist BU72 (Huang et al, 2015), as a template for generating multiple homology models. Alignment of the KOP and MOP receptor sequences using ClustalW revealed that KOP and MOP receptors possessed a 67% sequence identity and 81% sequence similarity after alignment (Supplementary Material Figure S2(a)).…”

Section: Model Designmentioning

confidence: 99%

Salvindolin elicits opioid system-mediated antinociceptive and antidepressant-like activities

et al. 2019

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Background: Salvinorin A is known as a highly selective kappa opioid receptor agonist with antinociceptive but mostly pro-depressive effects. Aims: In this article, we present its new semisynthetic analog with preferential mu opioid affinity, and promising antinociceptive, as well as antidepressant-like activities. Methods: Competitive binding studies were performed for salvindolin with kappa opioid and mu opioid. The mouse model of nociception (acetic-acid-induced writhing, formalin, and hot plate tests), depression (forced swim and tail suspension tests), and the open field test, were used to evaluate antinociceptive, antidepressant-like, and locomotion effects, respectively, of salvindolin. We built a 3-D molecular model of the kappa opioid receptor, using a mu opioid X-ray crystal structure as a template, and docked salvindolin into the two proteins. Results/outcomes: Salvindolin showed affinity towards kappa opioid and mu opioid receptors but with 100-fold mu opioid preference. Tests of salvindolin in mice revealed good oral bioavailability, antinociceptive, and antidepressive-like effects, without locomotor incoordination. Docking of salvindolin showed strong interactions with the mu opioid receptor which matched well with experimental binding data. Salvindolin-induced behavioral changes in the hot plate and forced swim tests were attenuated by naloxone (nonselective opioid receptor antagonist) and/or naloxonazine (selective mu opioid receptor antagonist) but not by nor-binaltorphimine (selective kappa opioid receptor antagonist). In addition, WAY100635 (a selective serotonin 1A receptor antagonist) blocked the antidepressant-like effect of salvindolin. Conclusions/interpretation: By simple chemical modification, we were able to modulate the pharmacological profile of salvinorin A, a highly selective kappa opioid receptor agonist, to salvindolin, a ligand with preferential mu opioid receptor affinity and activity on the serotonin 1A receptor. With its significant antinociceptive and antidepressive-like activities, salvindolin has the potential to be an analgesic and/or antidepressant drug candidate.

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