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Sci Adv. 2019 Nov 27;5(11):eaax9115. doi: 10.1126/sciadv.aax9115. eCollection 2019 Nov.

Elucidating the active δ-opioid receptor crystal structure with peptide and small-molecule agonists.

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iHuman Institute, ShanghaiTech University, Ren Building, 393 Middle Huaxia Rd, Pudong, Shanghai 201210, China.
PharmaCenter Bonn, University of Bonn, Pharmaceutical Chemistry I, An der Immenburg 4, D-53121 Bonn, Germany.
School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
University of the Chinese Academy of Sciences, Beijing 100049, China.
Department of Pharmacology-Physiology, Faculty of Medicine and Health Sciences, Institut de Pharmacologie de Sherbrooke, Centre de Recherche du CHUS, Université de Sherbrooke, 3001 12e Avenue Nord, Sherbrooke, Quebec J1H 5N4, Canada.
Departments of Biological Sciences and Chemistry, Bridge Institute, USC Michelson Center for Convergent Bioscience, University of Southern California, Los Angeles, CA 90089, USA.
Research Group of Organic Chemistry, Departments of Chemistry and Bioengineering Sciences, Vrije Universiteit Brussel, Pleinlaan 2, B-1050 Brussels, Belgium.
GPCR Consortium, San Marcos, CA 92078, USA.


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.

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