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- EMDB-66207: Cryo-EM structure of DAMGO-muOR-arrestin-1-Fab30 complex -

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Basic information

Entry
Database: EMDB / ID: EMD-66207
TitleCryo-EM structure of DAMGO-muOR-arrestin-1-Fab30 complex
Map data
Sample
  • Complex: Complex of DAMGO bound MOR-arrestin2 protein
    • Protein or peptide: Mu-type opioid receptor,Vasopressin V2 receptor
    • Protein or peptide: Beta-arrestin-1
    • Protein or peptide: Fab30 heavy chain
    • Protein or peptide: Fab30 light chain
    • Protein or peptide: DAMGO
  • Ligand: water
KeywordsG-protein-coupled receptors / mu-opioid receptor / single particle / Cryo-EM / MEMBRANE PROTEIN
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
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)
Methodsingle 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 support1 items
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, 2025-
Header (metadata) releaseNov 26, 2025-
Map releaseNov 26, 2025-
UpdateNov 26, 2025-
Current statusNov 26, 2025Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_66207.png

Downloads & links

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Map

FileDownload / File: emd_66207.map.gz / Format: CCP4 / Size: 91.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
0.93 Å/pix.
x 288 pix.
= 267.84 Å		0.93 Å/pix.
x 288 pix.
= 267.84 Å		0.93 Å/pix.
x 288 pix.
= 267.84 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.93 Å
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Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.005
Minimum - Maximum-0.043091815 - 0.059477612
Average (Standard dev.)0.00000033343002 (±0.0013306952)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions288288288
Spacing288288288
CellA=B=C: 267.84 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_66207_half_map_1.map
Projections & Slices
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Half map: #1

Fileemd_66207_half_map_2.map
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Sample components

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Entire : Complex of DAMGO bound MOR-arrestin2 protein

EntireName: Complex of DAMGO bound MOR-arrestin2 protein
Components
  • Complex: Complex of DAMGO bound MOR-arrestin2 protein
    • Protein or peptide: Mu-type opioid receptor,Vasopressin V2 receptor
    • Protein or peptide: Beta-arrestin-1
    • Protein or peptide: Fab30 heavy chain
    • Protein or peptide: Fab30 light chain
    • Protein or peptide: DAMGO
  • Ligand: water

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Supramolecule #1: Complex of DAMGO bound MOR-arrestin2 protein

SupramoleculeName: Complex of DAMGO bound MOR-arrestin2 protein / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#5
Source (natural)Organism: Mus musculus (house mouse)

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Macromolecule #1: Mu-type opioid receptor,Vasopressin V2 receptor

MacromoleculeName: Mu-type opioid receptor,Vasopressin V2 receptor / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 43.316148 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: GPMGPGNISD CSDPLAPASC SPAPGSWLNL SHVDGNQSDP CGPNRTGLGG SHSLCPQTGS PSMVTAITIM ALYSIVCVVG LFGNFLVMY VIVRYTKMKT ATNIYIFNLA LADALATSTL PFQSVNYLMG TWPFGNILCK IVISIDYYNM FTSIFTLCTM S VDRYIAVC ...String:
GPMGPGNISD CSDPLAPASC SPAPGSWLNL SHVDGNQSDP CGPNRTGLGG SHSLCPQTGS PSMVTAITIM ALYSIVCVVG LFGNFLVMY VIVRYTKMKT ATNIYIFNLA LADALATSTL PFQSVNYLMG TWPFGNILCK IVISIDYYNM FTSIFTLCTM S VDRYIAVC HPVKALDFRT PRNAKIVNVC NWILSSAIGL PVMFMATTKY RQGSIDCTLT FSHPTWYWEN LLKICVFIFA FI MPVLIIT VCYGLMILRL KSVRMLSGSK EKDRNLRRIT RMVLVVVAVF IVCWTPIHIY VIIKALITIP ETTFQTVSWH FCI ALGYTN SCLNPVLYAF LDENFKRCFR EFCICARGRT PPSLGPQDE(SEP) C(TPO)(TPO)A(SEP)(SEP)(SEP)LAK DTSSLEVLF Q

UniProtKB: Mu-type opioid receptor, Vasopressin V2 receptor

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Macromolecule #2: Beta-arrestin-1

MacromoleculeName: Beta-arrestin-1 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Bos taurus (domestic cattle)
Molecular weightTheoretical: 44.135273 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MGDKGTRVFK KASPNGKLTV YLGKRDFVDH IDLVEPVDGV VLVDPEYLKE RRVYVTLTCA FRYGREDLDV LGLTFRKDLF VANVQSFPP APEDKKPLTR LQERLIKKLG EHAYPFTFEI PPNLPCSVTL QPGPEDTGKA CGVDYEVKAF CAENLEEKIH K RNSVRLVI ...String:
MGDKGTRVFK KASPNGKLTV YLGKRDFVDH IDLVEPVDGV VLVDPEYLKE RRVYVTLTCA FRYGREDLDV LGLTFRKDLF VANVQSFPP APEDKKPLTR LQERLIKKLG EHAYPFTFEI PPNLPCSVTL QPGPEDTGKA CGVDYEVKAF CAENLEEKIH K RNSVRLVI EKVQYAPERP GPQPTAETTR QFLMSDKPLH LEASLDKEIY YHGEPISVNV HVTNNTNKTV KKIKISVRQY AD ICLFNTA QYKCPVAMEE ADDTVAPSST FCKVYTLTPF LANNREKRGL ALDGKLKHED TNLASSTLLR EGANREILGI IVS YKVKVK LVVSRGGLLG DLASSDVAVE LPFTLMHPKP KEEPPHREVP EHETPVDTNL IELDTNDDDA AAEDFAR

UniProtKB: Beta-arrestin-1

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Macromolecule #3: Fab30 heavy chain

MacromoleculeName: Fab30 heavy chain / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 25.333227 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MEISEVQLVE SGGGLVQPGG SLRLSCAASG FNVYSSSIHW VRQAPGKGLE WVASISSYYG YTYYADSVKG RFTISADTSK NTAYLQMNS LRAEDTAVYY CARSRQFWYS GLDYWGQGTL VTVSSASTKG PSVFPLAPSS KSTSGGTAAL GCLVKDYFPE P VTVSWNSG ...String:
MEISEVQLVE SGGGLVQPGG SLRLSCAASG FNVYSSSIHW VRQAPGKGLE WVASISSYYG YTYYADSVKG RFTISADTSK NTAYLQMNS LRAEDTAVYY CARSRQFWYS GLDYWGQGTL VTVSSASTKG PSVFPLAPSS KSTSGGTAAL GCLVKDYFPE P VTVSWNSG ALTSGVHTFP AVLQSSGLYS LSSVVTVPSS SLGTQTYICN VNHKPSNTKV DKKVEPKSCD KTENLYFQ

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Macromolecule #4: Fab30 light chain

MacromoleculeName: Fab30 light chain / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 23.56626 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MSDIQMTQSP SSLSASVGDR VTITCRASQS VSSAVAWYQQ KPGKAPKLLI YSASSLYSGV PSRFSGSRSG TDFTLTISSL QPEDFATYY CQQYKYVPVT FGQGTKVEIK RTVAAPSVFI FPPSDSQLKS GTASVVCLLN NFYPREAKVQ WKVDNALQSG N SQESVTEQ ...String:
MSDIQMTQSP SSLSASVGDR VTITCRASQS VSSAVAWYQQ KPGKAPKLLI YSASSLYSGV PSRFSGSRSG TDFTLTISSL QPEDFATYY CQQYKYVPVT FGQGTKVEIK RTVAAPSVFI FPPSDSQLKS GTASVVCLLN NFYPREAKVQ WKVDNALQSG N SQESVTEQ DSKDSTYSLS STLTLSKADY EKHKVYACEV THQGLSSPVT KSFNRGEC

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Macromolecule #5: DAMGO

MacromoleculeName: DAMGO / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 513.587 Da
SequenceString:
Y(DAL)G(MEA)(ETA)

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Macromolecule #6: water

MacromoleculeName: water / type: ligand / ID: 6 / Number of copies: 4 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER

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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: 7.4
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: 52.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.6 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: NONE
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.8 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION / Number images used: 233269
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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