9PPY

CryoEM structure of delta opioid receptor bound to G proteins and met-enkephalin

Summary for 9PPY

• Entry DOI: 10.2210/pdb9ppy/pdb
• EMDB information: 71778
• Descriptor: Delta-type opioid receptor, Guanine nucleotide-binding protein G(i) subunit alpha-1, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, ... (6 entities in total)
• Functional Keywords: gpcr, delta opioid receptor, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 146534.76

Authors

Fay, J.F.,Che, T. (deposition date: 2025-07-22, release date: 2026-03-04, Last modification date: 2026-04-08)

Primary citation

Bernhard, S.M.,Roy Chowdhury, S.,Murata, T.,Reinl, E.L.,Ramos-Gonzalez, N.,Denn, E.,Appourchaux, K.,Inoue, A.,England, S.K.,Fay, J.F.,Majumdar, S.,Chanda, B.,Che, T.
Mechanistic insights into the therapeutic properties of delta opioid receptor.
Sci Adv, 12:eaeb6737-eaeb6737, 2026

PubMed Abstract: 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.

PubMed: 41880505
DOI: 10.1126/sciadv.aeb6737

Experimental method

ELECTRON MICROSCOPY (3.1 Å)