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- EMDB-71775: Locally-refined Mu-Opioid Receptor bound with novel compound 0505 -

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Basic information

Entry
Database: EMDB / ID: EMD-71775
TitleLocally-refined Mu-Opioid Receptor bound with novel compound 0505
Map data
Sample
  • Complex: Active-state Mu-opioid receptor fused with miniG protein, bound with GBetaGamma, scFv16, and compound 0505
    • Protein or peptide: Mu-type opioid receptor
  • Ligand: 3-[({[(1P)-1-(3-chlorophenyl)-1H-pyrazol-3-yl]methyl}amino)methyl]phenol
KeywordsGPCR / Mu-Opioid / Partial Agonist / Active / MEMBRANE PROTEIN
Function / homology
Function and homology information


Opioid Signalling / beta-endorphin receptor activity / morphine receptor activity / negative regulation of Wnt protein secretion / regulation of cellular response to stress / G protein-coupled opioid receptor signaling pathway / behavioral response to ethanol / negative regulation of nitric oxide biosynthetic process / sensory perception / adenylate cyclase-inhibiting G protein-coupled acetylcholine receptor signaling pathway ...Opioid Signalling / beta-endorphin receptor activity / morphine receptor activity / negative regulation of Wnt protein secretion / regulation of cellular response to stress / G protein-coupled opioid receptor signaling pathway / behavioral response to ethanol / negative regulation of nitric oxide biosynthetic process / sensory perception / adenylate cyclase-inhibiting G protein-coupled acetylcholine receptor signaling pathway / regulation of NMDA receptor activity / neuropeptide binding / positive regulation of neurogenesis / negative regulation of cytosolic calcium ion concentration / G-protein alpha-subunit binding / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / neuropeptide signaling pathway / voltage-gated calcium channel activity / MECP2 regulates neuronal receptors and channels / sensory perception of pain / Peptide ligand-binding receptors / G protein-coupled receptor activity / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / G-protein activation / G-protein beta-subunit binding / Interleukin-4 and Interleukin-13 signaling / G alpha (i) signalling events / phospholipase C-activating G protein-coupled receptor signaling pathway / perikaryon / positive regulation of ERK1 and ERK2 cascade / endosome / neuron projection / G protein-coupled receptor signaling pathway / negative regulation of cell population proliferation / axon / dendrite / synapse / endoplasmic reticulum / Golgi apparatus / plasma membrane
Similarity search - Function
Mu opioid receptor / Opioid receptor / 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.
Similarity search - Domain/homology
Mu-type opioid receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.34 Å
AuthorsKim JY / Wu Y / Manglik A / Shoichet BK
Funding support United States, 2 items
OrganizationGrant numberCountry
Defense Advanced Research Projects Agency (DARPA)HR0011-19-2-0020 United States
ARPA-H1AY1AX000035 United States
CitationJournal: J Med Chem / Year: 2026
Title: Large Library Docking for Polypharmacology.
Authors: Yujin Wu / Seth Vigneron / Joao Braz / Karthik Srinivasan / Elissa A Fink / Xi-Ping Huang / Xinyu Xu / Harald Huebner / Joseph Y Kim / Jing Wang / Tara Pfeiffer / Kensuke Sakamoto / Dmytro S ...Authors: Yujin Wu / Seth Vigneron / Joao Braz / Karthik Srinivasan / Elissa A Fink / Xi-Ping Huang / Xinyu Xu / Harald Huebner / Joseph Y Kim / Jing Wang / Tara Pfeiffer / Kensuke Sakamoto / Dmytro S Radchenko / Ramona M Rodriguiz / Yurii S Moroz / John J Irwin / Peter Gmeiner / Christian Billesboelle / Bryan L Roth / Allan I Basbaum / Aashish Manglik / William C Wetsel / Brian K Shoichet /
Abstract: Polypharmacological molecules are attractive for complex illnesses. Here, we explored large library docking for joint activity against target pairs. Retrospectively, as libraries grew, so too did the ...Polypharmacological molecules are attractive for complex illnesses. Here, we explored large library docking for joint activity against target pairs. Retrospectively, as libraries grew, so too did the number of likely dual-activity molecules. In prospective docking of a 900-million molecule library against three target pairs (α/SERT, MOR/SERT, and α/MOR), we sought analgesic compounds. Both the α/SERT and SERT/MOR campaigns led to dual binders with low μM to high nM activities with high hit rates; tetrahydropyridines from the α/SERT campaign were also active against 5-HT. However, even though cryo-EM structures confirmed the docking-predicted poses, optimization struggled to improve potency. Still, in mouse behavioral assays, the most potent α/SERT compound (') was effective against pain without inducing conditioned place preference, and the molecule had potent antidepression and anxiolytic drug-like behavior, consistent with its SERT/5-HT activities. This study reveals both advantages and challenges of docking for polypharmacology.
History
DepositionJul 21, 2025-
Header (metadata) releaseMar 4, 2026-
Map releaseMar 4, 2026-
UpdateMar 4, 2026-
Current statusMar 4, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_71775.png

Downloads & links

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Map

FileDownload / File: emd_71775.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

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AxesZ (Sec.)Y (Row.)X (Col.)
0.82 Å/pix.
x 360 pix.
= 294.804 Å		0.82 Å/pix.
x 360 pix.
= 294.804 Å		0.82 Å/pix.
x 360 pix.
= 294.804 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.8189 Å
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Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.25
Minimum - Maximum-1.1744722 - 1.7703696
Average (Standard dev.)-0.00018176416 (±0.024297068)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 294.804 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_71775_msk_1.map
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Additional map: Full structure, prior to masked local refinement

Fileemd_71775_additional_1.map
AnnotationFull structure, prior to masked local refinement
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Half map: #1

Fileemd_71775_half_map_1.map
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Half map: #2

Fileemd_71775_half_map_2.map
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Sample components

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Entire : Active-state Mu-opioid receptor fused with miniG protein, bound w...

EntireName: Active-state Mu-opioid receptor fused with miniG protein, bound with GBetaGamma, scFv16, and compound 0505
Components
  • Complex: Active-state Mu-opioid receptor fused with miniG protein, bound with GBetaGamma, scFv16, and compound 0505
    • Protein or peptide: Mu-type opioid receptor
  • Ligand: 3-[({[(1P)-1-(3-chlorophenyl)-1H-pyrazol-3-yl]methyl}amino)methyl]phenol

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Supramolecule #1: Active-state Mu-opioid receptor fused with miniG protein, bound w...

SupramoleculeName: Active-state Mu-opioid receptor fused with miniG protein, bound with GBetaGamma, scFv16, and compound 0505
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 72.5 KDa

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Macromolecule #1: Mu-type opioid receptor

MacromoleculeName: Mu-type opioid receptor / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 38.145012 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: LALAIAITAL YSIVCVVGLF GNFLVMYVIV RYTKMKTATN IYIFNLALAD ALATSTLPFQ SVNYLMGTWP FGTILCKIVI SIDYYNMFT SIFTLCTMSV DRYIAVCHPV KALDFRTPRN AKIINVCNWI LSSAIGLPVM FMATTKYRQG SIDCTLTFSH P TWYWENLL ...String:
LALAIAITAL YSIVCVVGLF GNFLVMYVIV RYTKMKTATN IYIFNLALAD ALATSTLPFQ SVNYLMGTWP FGTILCKIVI SIDYYNMFT SIFTLCTMSV DRYIAVCHPV KALDFRTPRN AKIINVCNWI LSSAIGLPVM FMATTKYRQG SIDCTLTFSH P TWYWENLL KICVFIFAFI MPVLIITVCY GLMILRLKSV RMLSGSKEKD RNLRRITRMV LVVVAVFIVC WTPIHIYVII KA LVTIPET TFQTVSWHFC IALGYTNSCL NPVLYAFLDE NFKRCFREFC IPTSSNIEQQ NSTRIRQNTR DHPSTANTVD RTN HQLENL EAETAPLP

UniProtKB: Mu-type opioid receptor

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Macromolecule #2: 3-[({[(1P)-1-(3-chlorophenyl)-1H-pyrazol-3-yl]methyl}amino)methyl...

MacromoleculeName: 3-[({[(1P)-1-(3-chlorophenyl)-1H-pyrazol-3-yl]methyl}amino)methyl]phenol
type: ligand / ID: 2 / Number of copies: 1 / Formula: A1CIX
Molecular weightTheoretical: 313.781 Da

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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
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Support film - Material: GOLD / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Specialist opticsPhase plate: OTHER
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 47.7 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.1 µm / Nominal defocus min: 0.8 µm
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING ONLY
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

7t2g

Final reconstructionAlgorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 3.34 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 52988
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

7t2g


Chain - Source name: PDB / Chain - Initial model type: experimental model
RefinementSpace: REAL / Protocol: RIGID BODY FIT
Output model

PDB-9ppq:
Locally-refined Mu-Opioid Receptor bound with novel compound 0505 (3-[({[(1P)-1-(3-chlorophenyl)-1H-pyrazol-3-yl]methyl}amino)methyl]phenol)

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