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- EMDB-72829: receptor focused refinement of the human delta opioid complex wit... -

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Basic information

Entry
Database: EMDB / ID: EMD-72829
Titlereceptor focused refinement of the human delta opioid complex with mini-Gi, agonist DADLE and allosteric modulator MIPS3614
Map datareceptor focused map aligned to consensus map
Sample
  • Complex: Human delta opioid receptor complex with mini-Gi and agonist DADLE
KeywordsGPCR / opioid receptor / ligand binding / allosteric modulation / MEMBRANE PROTEIN
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.22 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_72829.png

Downloads & links

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Map

FileDownload / File: emd_72829.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationreceptor focused map aligned to consensus 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: 0.4
Minimum - Maximum-0.97149926 - 2.3179784
Average (Standard dev.)-0.00037764353 (±0.030670576)
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_72829_msk_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
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Additional map: original receptor focused map

Fileemd_72829_additional_1.map
Annotationoriginal receptor focused map
Projections & Slices
AxesZYX

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Histogram

Histogram (log scale)

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Half map: receptor focused half map 2

Fileemd_72829_half_map_1.map
Annotationreceptor focused half map 2
Projections & Slices
AxesZYX

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Density Histograms

Histogram

Histogram (log scale)

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Half map: receptor focused half map 1

Fileemd_72829_half_map_2.map
Annotationreceptor focused half 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

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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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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: 2.22 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 1165546
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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