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- PDB-9ppq: Locally-refined Mu-Opioid Receptor bound with novel compound 0505... -

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Basic information

Entry
Database: PDB / ID: 9ppq
TitleLocally-refined Mu-Opioid Receptor bound with novel compound 0505 (3-[({[(1P)-1-(3-chlorophenyl)-1H-pyrazol-3-yl]methyl}amino)methyl]phenol)
ComponentsMu-type opioid receptor
KeywordsMEMBRANE PROTEIN / GPCR / Mu-Opioid / Partial Agonist / Active
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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.34 Å
AuthorsKim, J.Y. / Wu, Y. / Manglik, A. / Shoichet, B.K.
Funding support United States, 2items
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, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 4, 2026Provider: repository / Type: Initial release
Revision 1.0Mar 4, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Mar 4, 2026Data content type: Additional map / Part number: 1 / Data content type: Additional map / Provider: repository / Type: Initial release
Revision 1.0Mar 4, 2026Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Mar 4, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Mar 4, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Mar 4, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Mar 4, 2026Data content type: Mask / Part number: 1 / Data content type: Mask / Provider: repository / Type: Initial release
Revision 1.0Mar 4, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
R: Mu-type opioid receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,4592
Polymers38,1451
Non-polymers3141
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Mu-type opioid receptor / M-OR-1 / MOR-1 / Mu opiate receptor / Mu opioid receptor / MOP / hMOP


Mass: 38145.012 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: OPRM1, MOR1 / Production host: Homo sapiens (human) / References: UniProt: P35372
#2: Chemical ChemComp-A1CIX / 3-[({[(1P)-1-(3-chlorophenyl)-1H-pyrazol-3-yl]methyl}amino)methyl]phenol


Mass: 313.781 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H16ClN3O / Feature type: SUBJECT OF INVESTIGATION
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: Active-state Mu-opioid receptor fused with miniG protein, bound with GBetaGamma, scFv16, and compound 0505
Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 0.0725 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE

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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: OTHER
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2100 nm / Nominal defocus min: 800 nm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 47.7 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)
EM imaging opticsPhase plate: OTHER

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Processing

EM software
IDNameVersionCategory
1cryoSPARCparticle selection
12cryoSPARC3D reconstruction
13PHENIX1.21.1_5286:model refinement
CTF correctionType: PHASE FLIPPING ONLY
3D reconstructionResolution: 3.34 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 52988 / Algorithm: FOURIER SPACE / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT / Space: REAL
Atomic model buildingPDB-ID: 7T2G

7t2g


Accession code: 7T2G / Source name: PDB / Type: experimental model
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0032339
ELECTRON MICROSCOPYf_angle_d0.5133192
ELECTRON MICROSCOPYf_dihedral_angle_d8.461315
ELECTRON MICROSCOPYf_chiral_restr0.037388
ELECTRON MICROSCOPYf_plane_restr0.004378

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