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Structure paper

TitleMechanistic insights into the therapeutic properties of delta opioid receptor.
Journal, issue, pagesSci Adv, Vol. 12, Issue 13, Page eaeb6737, Year 2026
Publish dateMar 27, 2026
AuthorsSarah M Bernhard / Susovan Roy Chowdhury / Tsuyoshi Murata / Erin L Reinl / Nokomis Ramos-Gonzalez / Elizabeth Denn / Kevin Appourchaux / Asuka Inoue / Sarah K England / Jonathan F Fay / Susruta Majumdar / Baron Chanda / Tao Che /
PubMed AbstractThe delta opioid receptor (DOR) is a promising target for treating pain, anxiety, and depression, yet no DOR-based drugs have reached the clinic. Here, we examine how ligands with varying therapeutic ...The delta opioid receptor (DOR) is a promising target for treating pain, anxiety, and depression, yet no DOR-based drugs have reached the clinic. Here, we examine how ligands with varying therapeutic properties modulate DOR function. While full agonists rapidly internalize the receptor, partial agonists show a slower rate of internalization, and antagonists increase cell-surface DOR levels. High-resolution structures of ligand-bound DOR-G complexes, including those with antagonists engaged, reveal key interactions that account for DOR ligand selectivity, potency, and efficacy. Single-molecule fluorescence resonance energy transfer studies show that DOR dynamically samples three distinct states (active, obligate preactive, and inactive), and transition rates are tuned by both ligand efficacy and G protein coupling. The endogenous agonist, met-enkephalin, not only stabilizes the active-state conformation but also catalyzes transitions between the active and inactive states. These results reveal how ligand-specific interactions and receptor dynamics can govern pharmacological profiles and provide a framework for developing DOR-targeted therapeutics.
External linksSci Adv / PubMed:41880505 / PubMed Central
MethodsEM (single particle)
Resolution3.04 - 3.32 Å
Structure data

EMDB-71776, PDB-9ppw:
CryoEM structure of delta opioid receptor bound to G proteins and Naltrindole
Method: EM (single particle) / Resolution: 3.32 Å

EMDB-71777, PDB-9ppx:
CryoEM structure of delta opioid receptor bound to G proteins and naltrexone
Method: EM (single particle) / Resolution: 3.04 Å

EMDB-71778, PDB-9ppy:
CryoEM structure of delta opioid receptor bound to G proteins and met-enkephalin
Method: EM (single particle) / Resolution: 3.1 Å

EMDB-71779, PDB-9ppz:
CryoEM structure of delta opioid receptor bound to G proteins and SNC80
Method: EM (single particle) / Resolution: 3.19 Å

EMDB-71780, PDB-9pq0:
CryoEM structure of delta opioid receptor bound to G proteins and ADL5859
Method: EM (single particle) / Resolution: 3.12 Å

Chemicals

ChemComp-EJ4:
(4bS,8R,8aS,14bR)-7-(cyclopropylmethyl)-5,6,7,8,14,14b-hexahydro-4,8-methano[1]benzofuro[2,3-a]pyrido[4,3-b]carbazole-1,8a(9H)-diol / antagonist*YM

PDB-1clj:
Unknown entry

PDB-1cli:
X-RAY CRYSTAL STRUCTURE OF AMINOIMIDAZOLE RIBONUCLEOTIDE SYNTHETASE (PURM), FROM THE E. COLI PURINE BIOSYNTHETIC PATHWAY, AT 2.5 A RESOLUTION

PDB-1lxy:
Crystal Structure of Arginine Deiminase covalently linked with L-citrulline

Source
  • homo sapiens (human)
  • mus musculus (house mouse)
KeywordsMEMBRANE PROTEIN / GPCR / Delta OPIOID Receptor

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