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- PDB-9ppx: CryoEM structure of delta opioid receptor bound to G proteins and... -

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Basic information

Entry
Database: PDB / ID: 9ppx
TitleCryoEM structure of delta opioid receptor bound to G proteins and naltrexone
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Delta-type opioid receptor
  • ScFv16 protein
KeywordsMEMBRANE PROTEIN / GPCR / Delta OPIOID Receptor
Function / homology
Function and homology information


G protein-coupled enkephalin receptor activity / spine apparatus / G protein-coupled opioid receptor activity / G protein-coupled opioid receptor signaling pathway / receptor serine/threonine kinase binding / cellular response to toxic substance / neuropeptide binding / eating behavior / regulation of calcium ion transport / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger ...G protein-coupled enkephalin receptor activity / spine apparatus / G protein-coupled opioid receptor activity / G protein-coupled opioid receptor signaling pathway / receptor serine/threonine kinase binding / cellular response to toxic substance / neuropeptide binding / eating behavior / regulation of calcium ion transport / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / neuronal dense core vesicle / negative regulation of protein-containing complex assembly / adenylate cyclase inhibitor activity / positive regulation of protein localization to cell cortex / T cell migration / positive regulation of relaxation of smooth muscle / Adenylate cyclase inhibitory pathway / D2 dopamine receptor binding / adenylate cyclase-inhibiting serotonin receptor signaling pathway / G protein-coupled serotonin receptor binding / dendrite membrane / axon terminus / cellular response to forskolin / Peptide ligand-binding receptors / regulation of mitotic spindle organization / chemokine-mediated signaling pathway / response to nicotine / regulation of mitochondrial membrane potential / adult locomotory behavior / Regulation of insulin secretion / neuropeptide signaling pathway / response to prostaglandin E / positive regulation of cholesterol biosynthetic process / negative regulation of insulin secretion / G protein-coupled receptor binding / postsynaptic density membrane / response to peptide hormone / cellular response to growth factor stimulus / G-protein beta/gamma-subunit complex binding / centriolar satellite / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / Olfactory Signaling Pathway / Activation of the phototransduction cascade / G protein-coupled acetylcholine receptor signaling pathway / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G-protein activation / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / Prostacyclin signalling through prostacyclin receptor / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / G beta:gamma signalling through BTK / photoreceptor disc membrane / ADP signalling through P2Y purinoceptor 12 / Sensory perception of sweet, bitter, and umami (glutamate) taste / Glucagon-type ligand receptors / GDP binding / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / G alpha (z) signalling events / cellular response to catecholamine stimulus / ADP signalling through P2Y purinoceptor 1 / ADORA2B mediated anti-inflammatory cytokines production / G beta:gamma signalling through PI3Kgamma / adenylate cyclase-activating dopamine receptor signaling pathway / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / cellular response to prostaglandin E stimulus / heterotrimeric G-protein complex / G alpha (12/13) signalling events / Inactivation, recovery and regulation of the phototransduction cascade / G-protein beta-subunit binding / synaptic vesicle membrane / extracellular vesicle / sensory perception of taste / sperm principal piece / Thrombin signalling through proteinase activated receptors (PARs) / signaling receptor complex adaptor activity / adenylate cyclase-activating G protein-coupled receptor signaling pathway / retina development in camera-type eye / GTPase binding / G protein activity / Interleukin-4 and Interleukin-13 signaling / fibroblast proliferation / presynaptic membrane / Ca2+ pathway / midbody / cell cortex / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / cellular response to hypoxia / G alpha (i) signalling events / G alpha (s) signalling events / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (q) signalling events / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement
Similarity search - Function
Delta opioid receptor / Opioid receptor / G-protein alpha subunit, group I / Serpentine type 7TM GPCR chemoreceptor Srsx / G protein alpha subunit, helical insertion / G protein alpha subunit / Guanine nucleotide binding protein (G-protein), alpha subunit / G-protein alpha subunit / G-alpha domain profile. / G-protein, gamma subunit ...Delta opioid receptor / Opioid receptor / G-protein alpha subunit, group I / Serpentine type 7TM GPCR chemoreceptor Srsx / G protein alpha subunit, helical insertion / G protein alpha subunit / Guanine nucleotide binding protein (G-protein), alpha subunit / G-protein alpha subunit / G-alpha domain profile. / G-protein, gamma subunit / G-protein gamma subunit domain profile. / G-protein gamma-like domain / G-protein gamma-like domain superfamily / GGL domain / G protein gamma subunit-like motifs / GGL domain / G protein beta WD-40 repeat protein / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / G-protein coupled receptors family 1 signature. / 7 transmembrane receptor (rhodopsin family) / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
: / Delta-type opioid receptor / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Guanine nucleotide-binding protein G(i) subunit alpha-1
Similarity search - Component
Biological speciesHomo sapiens (human)
Mus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.04 Å
AuthorsFay, J.F. / Che, T.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01DA057790 United States
CitationJournal: Sci Adv / Year: 2026
Title: Mechanistic insights into the therapeutic properties of delta opioid receptor.
Authors: Sarah 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 / ...Authors: Sarah 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 /
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 ...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.
History
DepositionJul 22, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 4, 2026Provider: repository / Type: Initial release
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Delta-type opioid receptor
B: Guanine nucleotide-binding protein G(i) subunit alpha-1
C: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
D: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
E: ScFv16 protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)146,3026
Polymers145,9615
Non-polymers3411
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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Guanine nucleotide-binding protein ... , 3 types, 3 molecules BCD

#2: Protein Guanine nucleotide-binding protein G(i) subunit alpha-1 / Adenylate cyclase-inhibiting G alpha protein


Mass: 40414.047 Da / Num. of mol.: 1 / Mutation: S47N, G203A, E245A, A326S
Source method: isolated from a genetically manipulated source
Details: Guanine nucleotide-binding protein G(i) subunit alpha-1
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAI1 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P63096, Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement
#3: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 37342.785 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
Source: (gene. exp.) Homo sapiens (human) / Gene: GNB1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P62873
#4: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


Mass: 7861.143 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNG2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P59768

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Protein / Antibody / Non-polymers , 3 types, 3 molecules AE

#1: Protein Delta-type opioid receptor / D-OR-1 / DOR-1


Mass: 33663.402 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: Delta-type opioid receptor / Source: (gene. exp.) Homo sapiens (human) / Gene: OPRD1, OPRD / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P41143
#5: Antibody ScFv16 protein


Mass: 26679.721 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: ScFv16 protein / Source: (gene. exp.) Mus musculus (house mouse) / Production host: Spodoptera frugiperda (fall armyworm)
#6: Chemical ChemComp-A1CLJ / 17-(cyclopropylmethyl)-3,14-dihydroxy-5alpha-4,5-epoxymorphinan-6-one


Mass: 341.401 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H23NO4

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Details

Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: CryoEM structure of delta opioid receptor bound to G proteins and naltrexone
Type: COMPLEX / Entity ID: #1-#5 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE-PROPANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2900 nm / Nominal defocus min: 600 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of real images: 3703

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Processing

EM software
IDNameVersionCategory
1cryoSPARCparticle selection
2cryoSPARC3.2image acquisition
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.04 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 225207 / Symmetry type: POINT
RefinementHighest resolution: 3.04 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0027041
ELECTRON MICROSCOPYf_angle_d0.4919646
ELECTRON MICROSCOPYf_dihedral_angle_d5.9451064
ELECTRON MICROSCOPYf_chiral_restr0.0411165
ELECTRON MICROSCOPYf_plane_restr0.0031220

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