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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 / Lysosome Vesicle Biogenesis / Defective AVP does not bind AVPR2 and causes neurohypophyseal diabetes insipidus (NDI) / spine apparatus / sperm ejaculation ...TGFBR3 regulates TGF-beta signaling / Opioid Signalling / MAP2K and MAPK activation / Activation of SMO / Golgi Associated Vesicle Biogenesis / renal water retention / Lysosome Vesicle Biogenesis / Defective AVP does not bind AVPR2 and causes neurohypophyseal diabetes insipidus (NDI) / spine apparatus / sperm ejaculation / regulation of systemic arterial blood pressure by vasopressin / Vasopressin-like receptors / renal water absorption / positive regulation of appetite / G-protein activation / Peptide ligand-binding receptors / vasopressin receptor activity / beta-endorphin receptor activity / morphine receptor activity / negative regulation of Wnt protein secretion / adenylate cyclase-inhibiting opioid receptor signaling pathway / AP-2 adaptor complex binding / Ub-specific processing proteases / clathrin coat of coated pit / negative regulation of luteinizing hormone secretion / Cargo recognition for clathrin-mediated endocytosis / clathrin heavy chain binding / telencephalon development / hemostasis / protein localization to non-motile cilium / G protein-coupled opioid receptor activity / G alpha (i) signalling events / G protein-coupled opioid receptor signaling pathway / Clathrin-mediated endocytosis / negative regulation of nitric oxide biosynthetic process / negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / desensitization of G protein-coupled receptor signaling pathway / adenylate cyclase-inhibiting G protein-coupled acetylcholine receptor signaling pathway / behavioral response to ethanol / acetylcholine receptor binding / clathrin-dependent endocytosis / G protein-coupled receptor internalization / positive regulation of neurogenesis / inositol hexakisphosphate binding / regulation of NMDA receptor activity / neuropeptide binding / negative regulation of Notch signaling pathway / Thrombin signalling through proteinase activated receptors (PARs) / G alpha (s) signalling events / sensory perception / eating behavior / clathrin binding / positive regulation of smoothened signaling pathway / small molecule binding / negative regulation of cytosolic calcium ion concentration / positive regulation of systemic arterial blood pressure / pseudopodium / positive regulation of intracellular signal transduction / phosphatidylinositol-3,4,5-trisphosphate binding / social behavior / regulation of cellular response to stress / positive regulation of receptor internalization / transmission of nerve impulse / positive regulation of vasoconstriction / G-protein alpha-subunit binding / endocytic vesicle / cellular response to hormone stimulus / activation of adenylate cyclase activity / positive regulation of gluconeogenesis / voltage-gated calcium channel activity / sensory perception of pain / presynaptic modulation of chemical synaptic transmission / T-tubule / locomotory behavior / dendrite cytoplasm / excitatory postsynaptic potential / dendrite membrane / sarcoplasmic reticulum / clathrin-coated endocytic vesicle membrane / neuropeptide signaling pathway / receptor internalization / GABA-ergic synapse / sarcolemma / positive regulation of protein phosphorylation / G protein-coupled receptor binding / G protein-coupled receptor activity / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / phospholipase C-activating G protein-coupled receptor signaling pathway / Vasopressin regulates renal water homeostasis via Aquaporins / Cargo recognition for clathrin-mediated endocytosis / adenylate cyclase-activating dopamine receptor signaling pathway / Clathrin-mediated endocytosis / G-protein beta-subunit binding / adenylate cyclase-activating G protein-coupled receptor signaling pathway / cytoplasmic vesicle / presynaptic membrane / ubiquitin-dependent protein catabolic process / G alpha (s) signalling events / molecular adaptor activity
Similarity search - Function
Vasopressin V2 receptor / Vasopressin receptor / Mu 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 ...Vasopressin V2 receptor / Vasopressin receptor / Mu 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 / Opioid receptor / Arrestin-like, C-terminal / G-protein coupled receptors family 1 signature. / Immunoglobulin E-set / 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
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
Revision 1.0Nov 26, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
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Revision 1.1Dec 24, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
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Revision 1.1Dec 24, 2025Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Database references / Experimental summary / Data content type: EM metadata / EM metadata / EM metadata / Category: citation / citation_author / em_admin
Data content type: EM metadata / EM metadata ...EM metadata / EM metadata / EM metadata / EM metadata / EM metadata
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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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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