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- PDB-9wsv: Cryo-EM structure of DAMGO-muOR-arrestin-1-Fab30 complex -

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Basic information

Entry
Database: PDB / ID: 9wsv
TitleCryo-EM structure of DAMGO-muOR-arrestin-1-Fab30 complex
Components
  • Beta-arrestin-1
  • DAMGO
  • Fab30 heavy chain
  • Fab30 light chain
  • Mu-type opioid receptor,Vasopressin V2 receptor
KeywordsMEMBRANE PROTEIN / G-protein-coupled receptors / mu-opioid receptor / single particle / Cryo-EM
Function / homology
Function and homology information


TGFBR3 regulates TGF-beta signaling / Opioid Signalling / MAP2K and MAPK activation / Activation of SMO / Golgi Associated Vesicle Biogenesis / renal water retention / Defective AVP does not bind AVPR2 and causes neurohypophyseal diabetes insipidus (NDI) / Vasopressin-like receptors / Lysosome Vesicle Biogenesis / regulation of systemic arterial blood pressure by vasopressin ...TGFBR3 regulates TGF-beta signaling / Opioid Signalling / MAP2K and MAPK activation / Activation of SMO / Golgi Associated Vesicle Biogenesis / renal water retention / Defective AVP does not bind AVPR2 and causes neurohypophyseal diabetes insipidus (NDI) / Vasopressin-like receptors / Lysosome Vesicle Biogenesis / regulation of systemic arterial blood pressure by vasopressin / vasopressin receptor activity / G-protein activation / beta-endorphin receptor activity / morphine receptor activity / negative regulation of Wnt protein secretion / Peptide ligand-binding receptors / G protein-coupled opioid receptor activity / AP-2 adaptor complex binding / Ub-specific processing proteases / clathrin coat of coated pit / clathrin heavy chain binding / Cargo recognition for clathrin-mediated endocytosis / G protein-coupled opioid receptor signaling pathway / hemostasis / desensitization of G protein-coupled receptor signaling pathway / telencephalon development / G alpha (i) signalling events / Clathrin-mediated endocytosis / negative regulation of nitric oxide biosynthetic process / clathrin-dependent endocytosis / adenylate cyclase-inhibiting G protein-coupled acetylcholine receptor signaling pathway / acetylcholine receptor binding / G protein-coupled receptor internalization / regulation of NMDA receptor activity / inositol hexakisphosphate binding / positive regulation of neurogenesis / Thrombin signalling through proteinase activated receptors (PARs) / G alpha (s) signalling events / clathrin binding / negative regulation of cytosolic calcium ion concentration / small molecule binding / positive regulation of vasoconstriction / pseudopodium / transmission of nerve impulse / positive regulation of systemic arterial blood pressure / phosphatidylinositol-3,4,5-trisphosphate binding / positive regulation of intracellular signal transduction / positive regulation of receptor internalization / negative regulation of Notch signaling pathway / endocytic vesicle / G-protein alpha-subunit binding / activation of adenylate cyclase activity / cellular response to hormone stimulus / response to cytokine / sensory perception of pain / presynaptic modulation of chemical synaptic transmission / locomotory behavior / clathrin-coated endocytic vesicle membrane / G protein-coupled receptor binding / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / G protein-coupled receptor activity / GABA-ergic synapse / receptor internalization / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / positive regulation of protein phosphorylation / Vasopressin regulates renal water homeostasis via Aquaporins / adenylate cyclase-activating dopamine receptor signaling pathway / Cargo recognition for clathrin-mediated endocytosis / presynapse / protein transport / Clathrin-mediated endocytosis / cytoplasmic vesicle / ubiquitin-dependent protein catabolic process / perikaryon / G alpha (s) signalling events / phospholipase C-activating G protein-coupled receptor signaling pathway / molecular adaptor activity / positive regulation of ERK1 and ERK2 cascade / endosome / G protein-coupled receptor signaling pathway / negative regulation of cell population proliferation / axon / positive regulation of cell population proliferation / dendrite / positive regulation of gene expression / perinuclear region of cytoplasm / endoplasmic reticulum / Golgi apparatus / signal transduction / nucleus / membrane / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Vasopressin V2 receptor / Vasopressin receptor / Mu opioid receptor / Opioid receptor / Arrestin, conserved site / Arrestins signature. / Arrestin / Arrestin, N-terminal / Arrestin-like, N-terminal / Arrestin C-terminal-like domain ...Vasopressin V2 receptor / Vasopressin receptor / Mu opioid receptor / Opioid receptor / Arrestin, conserved site / Arrestins signature. / Arrestin / Arrestin, N-terminal / Arrestin-like, N-terminal / Arrestin C-terminal-like domain / Arrestin (or S-antigen), N-terminal domain / Arrestin (or S-antigen), C-terminal domain / Arrestin (or S-antigen), C-terminal domain / Arrestin-like, C-terminal / 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) / Immunoglobulin E-set
Similarity search - Domain/homology
DAMGO / Beta-arrestin-1 / Vasopressin V2 receptor / Mu-type opioid receptor
Similarity search - Component
Biological speciesMus musculus (house mouse)
Homo sapiens (human)
Bos taurus (domestic cattle)
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.8 Å
AuthorsZhang, H. / Wang, X. / Xi, K. / Shen, Q. / Xue, J. / Zhu, Y. / Yang, G. / Zhang, Y.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Cell Res / Year: 2025
Title: The molecular basis of μ-opioid receptor signaling plasticity.
Authors: Huibing Zhang / Xueting Wang / Kun Xi / Qingya Shen / Jianheng Xue / Yanqing Zhu / Shao-Kun Zang / Tianqiang Yu / Dan-Dan Shen / Jia Guo / Li-Nan Chen / Su-Yu Ji / Jiao Qin / Yingjun Dong / ...Authors: Huibing Zhang / Xueting Wang / Kun Xi / Qingya Shen / Jianheng Xue / Yanqing Zhu / Shao-Kun Zang / Tianqiang Yu / Dan-Dan Shen / Jia Guo / Li-Nan Chen / Su-Yu Ji / Jiao Qin / Yingjun Dong / Mingming Zhao / Ming Yang / Haijing Wu / Guoli Yang / Yan Zhang /
Abstract: Activation of the μ-opioid receptor (μOR) alleviates pain but also elicits adverse effects through diverse G proteins and β-arrestins. The structural details of μOR complexes with G and β- ...Activation of the μ-opioid receptor (μOR) alleviates pain but also elicits adverse effects through diverse G proteins and β-arrestins. The structural details of μOR complexes with G and β-arrestins have not been determined, impeding a comprehensive understanding of μOR signaling plasticity. Here, we present the cryo-EM structures of the μOR-G and μOR-βarr1 complexes, revealing selective conformational preferences of μOR when engaged with specific downstream signaling transducers. Integrated receptor pharmacology, including high-resolution structural analysis, cell signaling assays, and molecular dynamics simulations, demonstrated that transmembrane helix 1 (TM1) acts as an allosteric regulator of μOR signaling bias through differential stabilization of the G-, G-, and βarr1-bound states. Mechanistically, outward TM1 displacement confers structural flexibility that promotes G protein recruitment, whereas inward TM1 retraction facilitates βarr1 recruitment by stabilizing the intracellular binding pocket through coordinated interactions with TM2, TM7, and helix8. Structural comparisons between the G-, G-, and βarr1-bound complexes identified a TM1-fusion pocket with significant implications for downstream signaling regulation. Overall, we demonstrate that the conformational and thermodynamic heterogeneity of TM1 allosterically drives the downstream signaling specificity and plasticity of μOR, thereby expanding the understanding of μOR signal transduction mechanisms and providing new avenues for the rational design of analgesics.
History
DepositionSep 15, 2025Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Nov 26, 2025Provider: 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,Vasopressin V2 receptor
C: Beta-arrestin-1
H: Fab30 heavy chain
L: Fab30 light chain
P: DAMGO


Theoretical massNumber of molelcules
Total (without water)136,8645
Polymers136,8645
Non-polymers00
Water724
1


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

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Components

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Protein , 2 types, 2 molecules RC

#1: Protein Mu-type opioid receptor,Vasopressin V2 receptor / M-OR-1 / MOR-1 / V2R / AVPR V2 / Antidiuretic hormone receptor / Renal-type arginine vasopressin receptor


Mass: 43316.148 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse), (gene. exp.) Homo sapiens (human)
Gene: Oprm1, Mor, Oprm, AVPR2, ADHR, DIR, DIR3, V2R / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P42866, UniProt: P30518
#2: Protein Beta-arrestin-1 / Arrestin beta-1 / Arrestin-2


Mass: 44135.273 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Bos taurus (domestic cattle) / Gene: ARRB1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P17870

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Antibody , 2 types, 2 molecules HL

#3: Antibody Fab30 heavy chain


Mass: 25333.227 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) synthetic construct (others) / Production host: Escherichia coli (E. coli)
#4: Antibody Fab30 light chain


Mass: 23566.260 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) synthetic construct (others) / Production host: Escherichia coli (E. coli)

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Protein/peptide / Non-polymers , 2 types, 5 molecules P

#5: Protein/peptide DAMGO


Type: Peptide-like / Class: Synthetic opioid / Mass: 513.587 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others) / References: DAMGO
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 4 / Source method: isolated from a natural source / Formula: H2O

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Details

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: Complex of DAMGO bound MOR-arrestin2 protein / Type: COMPLEX / Entity ID: #1-#5 / Source: RECOMBINANT
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
21Mus musculus (house mouse)10090
31Bos taurus (domestic cattle)9913
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
21Spodoptera frugiperda (fall armyworm)7108
31Escherichia coli (E. coli)562
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen 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: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 600 nm
Image recordingElectron dose: 52 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

EM software
IDNameVersionCategory
1cryoSPARCparticle selection
2PHENIX1.19.2_4158model refinement
13RELION3D reconstruction
CTF correctionType: NONE
3D reconstructionResolution: 2.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 233269 / Symmetry type: POINT
RefinementHighest resolution: 2.8 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0047801
ELECTRON MICROSCOPYf_angle_d0.71110660
ELECTRON MICROSCOPYf_dihedral_angle_d12.4322689
ELECTRON MICROSCOPYf_chiral_restr0.0471276
ELECTRON MICROSCOPYf_plane_restr0.0051332

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