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- EMDB-72827: Human delta opioid receptor complex with mini-Gi and agonist DADL... -

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Basic information

Entry
Database: EMDB / ID: EMD-72827
TitleHuman delta opioid receptor complex with mini-Gi and agonist DADLE and allosteric modulator MIPS3983
Map dataConsensus map
Sample
  • Complex: Human delta opioid receptor complex with mini-Gi and agonist DADLE
    • Protein or peptide: Guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Protein or peptide: Nanobody 35
    • Protein or peptide: DADLE
    • Protein or peptide: OPRD1 isoform 1
  • Ligand: ethyl 3-[(8aS,9S,10S)-9-{4-[(2-cyclopropylphenyl)methoxy]phenyl}-6,6-dimethyl-8-oxo-7,8,8a,9-tetrahydrotetrazolo[5,1-b]quinazolin-4(6H)-yl]propanoate
  • Ligand: water
KeywordsGPCR / opioid receptor / ligand binding / allosteric modulation / MEMBRANE PROTEIN
Function / homology
Function and homology information


G protein-coupled enkephalin receptor activity / cellular response to toxic substance / neuropeptide signaling pathway / neuronal dense core vesicle / negative regulation of protein-containing complex assembly / adult locomotory behavior / regulation of mitochondrial membrane potential / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / Olfactory Signaling Pathway / Activation of the phototransduction cascade ...G protein-coupled enkephalin receptor activity / cellular response to toxic substance / neuropeptide signaling pathway / neuronal dense core vesicle / negative regulation of protein-containing complex assembly / adult locomotory behavior / regulation of mitochondrial membrane potential / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / Olfactory Signaling Pathway / Activation of the phototransduction cascade / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / G protein-coupled acetylcholine receptor signaling pathway / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G-protein activation / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through CDC42 / Glucagon signaling in metabolic regulation / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / ADP signalling through P2Y purinoceptor 12 / photoreceptor disc membrane / Sensory perception of sweet, bitter, and umami (glutamate) taste / Glucagon-type ligand receptors / 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 / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / adenylate cyclase-activating dopamine receptor signaling pathway / GPER1 signaling / G-protein beta-subunit binding / cellular response to prostaglandin E stimulus / Inactivation, recovery and regulation of the phototransduction cascade / heterotrimeric G-protein complex / G alpha (12/13) signalling events / sensory perception of taste / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / retina development in camera-type eye / GTPase binding / Ca2+ pathway / fibroblast proliferation / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / G alpha (i) signalling events / cellular response to hypoxia / G alpha (s) signalling events / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (q) signalling events / Ras protein signal transduction / Extra-nuclear estrogen signaling / cell population proliferation / G protein-coupled receptor signaling pathway / negative regulation of gene expression / lysosomal membrane / GTPase activity / synapse / protein-containing complex binding / signal transduction / extracellular exosome / membrane / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Delta opioid receptor / Opioid receptor / Serpentine type 7TM GPCR chemoreceptor Srsx / 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 ...Delta opioid receptor / Opioid receptor / Serpentine type 7TM GPCR chemoreceptor Srsx / 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. / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / 7 transmembrane receptor (rhodopsin family) / 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
Similarity search - Domain/homology
OPRD1 isoform 1 / 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
Similarity search - Component
Biological speciesHomo sapiens (human) / Lama glama (llama)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.14 Å
AuthorsMobbs JI / Venugopal H / Thal DM
Funding support Australia, 2 items
OrganizationGrant numberCountry
National Health and Medical Research Council (NHMRC, Australia)2021675 Australia
National Health and Medical Research Council (NHMRC, Australia)1196951 Australia
CitationJournal: bioRxiv / Year: 2025
Title: Structure-guided allosteric modulation of the delta opioid receptor.
Authors: Jesse I Mobbs / M Deborah Nguyen / Owindeep Deo / Damian Bartuzi / Hariprasad Venugopal / Sadia Alvi / Vi Pham / Nick Barnes / Arthur Christopoulos / Daniel P Poole / Simona E Carbone / ...Authors: Jesse I Mobbs / M Deborah Nguyen / Owindeep Deo / Damian Bartuzi / Hariprasad Venugopal / Sadia Alvi / Vi Pham / Nick Barnes / Arthur Christopoulos / Daniel P Poole / Simona E Carbone / Manuela Jörg / Ben Capuano / Jens Carlsson / Arisbel B Gondin / Peter J Scammells / Celine Valant / David M Thal /
Abstract: Opioid analgesics remain essential for pain management but are associated with significant adverse effects, including respiratory depression, tolerance, and dependence. The δ-opioid receptor (δOR) ...Opioid analgesics remain essential for pain management but are associated with significant adverse effects, including respiratory depression, tolerance, and dependence. The δ-opioid receptor (δOR) represents a promising therapeutic target for developing safer opioid analgesics with reduced adverse effects compared to conventional μ-opioid receptor-targeting drugs. Positive allosteric modulators (PAMs) offer advantages over direct agonists by enhancing endogenous opioid signaling while preserving natural spatiotemporal activation patterns, potentially avoiding tolerance and dependence issues. Here, we present high-resolution cryo-EM structures of δOR complexed with the peptide agonist DADLE and the PAM MIPS3614, revealing a novel lipid-facing allosteric binding site formed by transmembrane helices 2, 3, and 4. MIPS3614 stabilizes the active receptor conformation through a critical hydrogen bond with residue N131 in the conserved sodium binding site, a key regulatory region controlling GPCR activation. Comprehensive mutagenesis, molecular dynamics simulations, and structure-activity relationships validate this proposed mechanism. Structure-guided optimization yielded MIPS3983 with enhanced binding affinity and retained cooperativity. Our findings establish the first molecular framework for δOR allosteric modulation and provide a structural foundation for the rational design of safer opioid therapeutics.
History
DepositionSep 23, 2025-
Header (metadata) releaseDec 10, 2025-
Map releaseDec 10, 2025-
UpdateDec 10, 2025-
Current statusDec 10, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_72827.png

Downloads & links

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Map

FileDownload / File: emd_72827.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationConsensus map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.82 Å/pix.
x 360 pix.
= 295.2 Å		0.82 Å/pix.
x 360 pix.
= 295.2 Å		0.82 Å/pix.
x 360 pix.
= 295.2 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.82 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.2
Minimum - Maximum-0.33149597 - 0.8424772
Average (Standard dev.)-0.000037357808 (±0.01612289)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 295.2 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_72827_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: half map 2

Fileemd_72827_half_map_1.map
Annotationhalf map 2
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: half map 1

Fileemd_72827_half_map_2.map
Annotationhalf map 1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Human delta opioid receptor complex with mini-Gi and agonist DADLE

EntireName: Human delta opioid receptor complex with mini-Gi and agonist DADLE
Components
  • Complex: Human delta opioid receptor complex with mini-Gi and agonist DADLE
    • Protein or peptide: Guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Protein or peptide: Nanobody 35
    • Protein or peptide: DADLE
    • Protein or peptide: OPRD1 isoform 1
  • Ligand: ethyl 3-[(8aS,9S,10S)-9-{4-[(2-cyclopropylphenyl)methoxy]phenyl}-6,6-dimethyl-8-oxo-7,8,8a,9-tetrahydrotetrazolo[5,1-b]quinazolin-4(6H)-yl]propanoate
  • Ligand: water

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Supramolecule #1: Human delta opioid receptor complex with mini-Gi and agonist DADLE

SupramoleculeName: Human delta opioid receptor complex with mini-Gi and agonist DADLE
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#6
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 150 KDa

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Macromolecule #1: Guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas

MacromoleculeName: Guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
EC number: Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 27.915672 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: GCTLSAEDKA AVERSKMIDR NLREDGEKAA REVKLLLLGA DNSGKSTIVK QMRILHGGSG GSGGTSGIFE TKFQVDKVNF HMFDVGGQR DERRKWIQCF NDVTAIIFVV DSSDYNRLQE ALNLFKSIWN NRWLRTISVI LFLNKQDLLA EKVLAGKSKI E DYFPEFAR ...String:
GCTLSAEDKA AVERSKMIDR NLREDGEKAA REVKLLLLGA DNSGKSTIVK QMRILHGGSG GSGGTSGIFE TKFQVDKVNF HMFDVGGQR DERRKWIQCF NDVTAIIFVV DSSDYNRLQE ALNLFKSIWN NRWLRTISVI LFLNKQDLLA EKVLAGKSKI E DYFPEFAR YTTPEDATPE PGEDPRVTRA KYFIRDEFLR ISTASGDGRH YCYPHFTCAV DTENARRIFN DVTDIIIKMN LR DCGLF

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Macromolecule #2: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1

MacromoleculeName: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 38.534062 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: MHHHHHHGSS GSELDQLRQE AEQLKNQIRD ARKACADATL SQITNNIDPV GRIQMRTRRT LRGHLAKIYA MHWGTDSRLL VSASQDGKL IIWDSYTTNK VHAIPLRSSW VMTCAYAPSG NYVACGGLDN ICSIYNLKTR EGNVRVSREL AGHTGYLSCC R FLDDNQIV ...String:
MHHHHHHGSS GSELDQLRQE AEQLKNQIRD ARKACADATL SQITNNIDPV GRIQMRTRRT LRGHLAKIYA MHWGTDSRLL VSASQDGKL IIWDSYTTNK VHAIPLRSSW VMTCAYAPSG NYVACGGLDN ICSIYNLKTR EGNVRVSREL AGHTGYLSCC R FLDDNQIV TSSGDTTCAL WDIETGQQTT TFTGHTGDVM SLSLAPDTRL FVSGACDASA KLWDVREGMC RQTFTGHESD IN AICFFPN GNAFATGSDD ATCRLFDLRA DQELMTYSHD NIICGITSVS FSKSGRLLLA GYDDFNCNVW DALKADRAGV LAG HDNRVS CLGVTDDGMA VATGSWDSFL KIWN

UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1

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Macromolecule #3: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2

MacromoleculeName: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 7.861143 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString:
MASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFCAI L

UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2

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Macromolecule #4: Nanobody 35

MacromoleculeName: Nanobody 35 / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Lama glama (llama)
Molecular weightTheoretical: 16.926076 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
MKYLLPTAAA GLLLLAAQPA MAQVQLQESG GGLVQPGGSL RLSCAASGFT FSNYKMNWVR QAPGKGLEWV SDISQSGASI SYTGSVKGR FTISRDNAKN TLYLQMNSLK PEDTAVYYCA RCPAPFTRDC FDVTSTTYAY RGQGTQVTVS SHHHHHH

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Macromolecule #5: DADLE

MacromoleculeName: DADLE / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 569.65 Da
SequenceString:
Y(DAL)GF(DLE)

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Macromolecule #6: OPRD1 isoform 1

MacromoleculeName: OPRD1 isoform 1 / type: protein_or_peptide / ID: 6 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 42.363539 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: DYKDDDDAEP APSAGAELQP PLFANASDAY PSAFPSAGAN ASGPPGARSA SSLALAIAIT ALYSAVCAVG LLGNVLVMFG IVRYTKMKT ATNIYIFNLA LADALATSTL PFQSAKYLME TWPFGELLCK AVLSIDYYNM FTSIFTLTMM SVDRYIAVCH P VKALDFRT ...String:
DYKDDDDAEP APSAGAELQP PLFANASDAY PSAFPSAGAN ASGPPGARSA SSLALAIAIT ALYSAVCAVG LLGNVLVMFG IVRYTKMKT ATNIYIFNLA LADALATSTL PFQSAKYLME TWPFGELLCK AVLSIDYYNM FTSIFTLTMM SVDRYIAVCH P VKALDFRT PAKAKLINIC IWVLASGVGV PIMVMAVTRP RDGAVVCMLQ FPSPSWYWDT VTKICVFLFA FVVPILIITV CY GLMLLRL RSVRLLSGSK EKDRSLRRIT RMVLVVVGAF VVCWAPIHIF VIVWTLVDID RRDPLVVAAL HLCIALGYAN SSL NPVLYA FLDENFKRCF RQLCRKPCGR PDPSSFSRAR EATARERVTA CTPSDGPGGG AAAHHHHHHH H

UniProtKB: OPRD1 isoform 1

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Macromolecule #7: ethyl 3-[(8aS,9S,10S)-9-{4-[(2-cyclopropylphenyl)methoxy]phenyl}-...

MacromoleculeName: ethyl 3-[(8aS,9S,10S)-9-{4-[(2-cyclopropylphenyl)methoxy]phenyl}-6,6-dimethyl-8-oxo-7,8,8a,9-tetrahydrotetrazolo[5,1-b]quinazolin-4(6H)-yl]propanoate
type: ligand / ID: 7 / Number of copies: 1 / Formula: A1CU8
Molecular weightTheoretical: 541.641 Da

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Macromolecule #8: water

MacromoleculeName: water / type: ligand / ID: 8 / Number of copies: 93 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.5 µm / Nominal defocus min: 0.5 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.14 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 319776
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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