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- EMDB-66831: The receptor local map of Leu-enkephalin-BMS-986187-bound DOR-Gi ... -

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Basic information

Entry
Database: EMDB / ID: EMD-66831
TitleThe receptor local map of Leu-enkephalin-BMS-986187-bound DOR-Gi complex
Map data
Sample
  • Complex: DOR in complex with Gi heterotrimer
KeywordsComplex / PAM / Agonist / MEMBRANE PROTEIN
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.22 Å
AuthorsZhao C / Fu H / Tian XW / Cheng L / Yan W / Shao ZH
Funding support China, 2 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)32371288 China
National Natural Science Foundation of China (NSFC)323B2038 China
CitationJournal: Signal Transduct Target Ther / Year: 2026
Title: Molecular mechanism of allosteric modulation of opioid receptors.
Authors: Heli Wang / Zhuang Miao / Chang Zhao / Hong Fu / Xiaowen Tian / Xinlei Liu / Lei Wang / Yuan Liu / Xingyu Liu / Xihao Yong / Lantian Su / Wei Yan / Lin Cheng / Renjie Chai / Zhenhua Shao / Bowen Ke /
Abstract: Opioid analgesics provide potent pain relief but are limited by severe adverse effects, tolerance, and interindividual genetic variability in response. Poly-pharmacology and allosteric modulation of ...Opioid analgesics provide potent pain relief but are limited by severe adverse effects, tolerance, and interindividual genetic variability in response. Poly-pharmacology and allosteric modulation of opioid receptors offer promising strategies to enhance analgesic efficacy while mitigating these limitations. Pan-positive allosteric modulators (pan-PAMs), which simultaneously potentiate multiple opioid receptor subtypes, integrate the advantages of both approaches and represent an emerging therapeutic paradigm for pain management. However, the molecular mechanisms underlying pan-PAM activity at opioid receptors remain poorly understood. Here, we characterize BMS-986187 as a pan-PAM of opioid receptors and report the cryo-electron microscopy (cryo-EM) structures of multiple opioid receptor subtypes bound to this modulator, revealing a previously unidentified allosteric pocket. Structural and functional analyses revealed a conserved binding motif that mediates PAM recognition across the opioid receptor family and revealed the essential contributions of key opioid receptor residues to allosteric modulation by BMS-986187. Functionally, BMS-986187 enhances analgesic efficacy through an opioid-sparing effect, allowing lower opioid doses and reducing side effects, while restoring activity in loss-of-function (LOF) μ-opioid receptor variants. These findings define a previously unrecognized allosteric site in opioid receptors and establish a structural framework for the rational design of safer and more effective opioid therapeutics through allosteric modulation.
History
DepositionOct 29, 2025-
Header (metadata) releaseJul 8, 2026-
Map releaseJul 8, 2026-
UpdateJul 8, 2026-
Current statusJul 8, 2026Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_66831.png

Downloads & links

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Map

FileReleased
Projections & slices

Image control

Size
Brightness
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Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.75 Å/pix.
x 300 pix.
= 225. Å		0.75 Å/pix.
x 300 pix.
= 225. Å		0.75 Å/pix.
x 300 pix.
= 225. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.75 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.15
Minimum - Maximum-1.1205488 - 1.3995738
Average (Standard dev.)-0.00028506358 (±0.017352177)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 225.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_66831_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_66831_half_map_2.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : DOR in complex with Gi heterotrimer

EntireName: DOR in complex with Gi heterotrimer
Components
  • Complex: DOR in complex with Gi heterotrimer

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Supramolecule #1: DOR in complex with Gi heterotrimer

SupramoleculeName: DOR in complex with Gi heterotrimer / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #4, #1-#3
Source (natural)Organism: Homo sapiens (human)

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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: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 1.4000000000000001 µm / Nominal defocus min: 0.8 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: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.22 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 518084
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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