How μ-opioid receptor recognizes fentanyl
| Autor: | Christopher R. Ellis, Paween Mahinthichaichan, Quynh N. Vo, Jana Shen |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Models Molecular Agonist Morphinan medicine.drug_class Stereochemistry Science Receptors Opioid mu General Physics and Astronomy Molecular Dynamics Simulation Ligands 01 natural sciences General Biochemistry Genetics and Molecular Biology Article Fentanyl 03 medical and health sciences Structure-Activity Relationship chemistry.chemical_compound Computational biophysics Opioid receptor 0103 physical sciences medicine Structure–activity relationship Receptor G protein-coupled receptor Multidisciplinary 010304 chemical physics Morphine Ligand General Chemistry Ligand (biochemistry) Tautomer Analgesics Opioid 030104 developmental biology Opioid chemistry Biophysical models medicine.drug |
| Zdroj: | Nature Communications Research Square article-version (status) pre article-version (number) 1 Nature Communications, Vol 12, Iss 1, Pp 1-11 (2021) bioRxiv article-version (number) 2 |
| ISSN: | 2041-1723 |
| Popis: | 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. Structures of mu-opioid receptor (mOR) in complex with morphine derivatives have been determined; but the structural basis of mOR activation by fentanyl-like synthetic opioids remains unclear. Here, authors use state-of-the-art simulation techniques and discover a secondary binding mode which is only accessible when the conserved His297 adopts a neutral HID tautomer state. |
| Databáze: | OpenAIRE |
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