Elucidating the active δ-opioid receptor crystal structure with peptide and small-molecule agonists.
Journal
Science advances
ISSN: 2375-2548
Titre abrégé: Sci Adv
Pays: United States
ID NLM: 101653440
Informations de publication
Date de publication:
11 2019
11 2019
Historique:
received:
03
05
2019
accepted:
25
09
2019
entrez:
7
12
2019
pubmed:
7
12
2019
medline:
21
5
2020
Statut:
epublish
Résumé
Selective activation of the δ-opioid receptor (DOP) has great potential for the treatment of chronic pain, benefitting from ancillary anxiolytic and antidepressant-like effects. Moreover, DOP agonists show reduced adverse effects as compared to μ-opioid receptor (MOP) agonists that are in the spotlight of the current "opioid crisis." Here, we report the first crystal structures of the DOP in an activated state, in complex with two relevant and structurally diverse agonists: the potent opioid agonist peptide KGCHM07 and the small-molecule agonist DPI-287 at 2.8 and 3.3 Å resolution, respectively. Our study identifies key determinants for agonist recognition, receptor activation, and DOP selectivity, revealing crucial differences between both agonist scaffolds. Our findings provide the first investigation into atomic-scale agonist binding at the DOP, supported by site-directed mutagenesis and pharmacological characterization. These structures will underpin the future structure-based development of DOP agonists for an improved pain treatment with fewer adverse effects.
Identifiants
pubmed: 31807708
doi: 10.1126/sciadv.aax9115
pii: aax9115
pmc: PMC6881160
doi:
Substances chimiques
OPRM1 protein, human
0
Peptides
0
Receptors, Opioid, delta
0
Receptors, Opioid, mu
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
eaax9115Subventions
Organisme : NIDA NIH HHS
ID : P01 DA035764
Pays : United States
Organisme : NIDA NIH HHS
ID : R33 DA038858
Pays : United States
Organisme : NIDA NIH HHS
ID : R21 DA038858
Pays : United States
Informations de copyright
Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).
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