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- EMDB-66205: Cryo-EM structure of DAMGO-muOR-Gz-scFv16 complex -

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Entry
Database: EMDB / ID: EMD-66205
TitleCryo-EM structure of DAMGO-muOR-Gz-scFv16 complex
Map data
Sample
  • Complex: Complex of DAMGO bound MOR-Gz protein
    • Protein or peptide: Engineered guanine nucleotide-binding protein G(z) subunit alpha
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Protein or peptide: Mu-type opioid receptor,LgBiT
  • 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


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 / Olfactory Signaling Pathway / Activation of the phototransduction cascade / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / G protein-coupled acetylcholine receptor signaling pathway / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G-protein activation / G beta:gamma signalling through CDC42 / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / ADP signalling through P2Y purinoceptor 12 / photoreceptor disc membrane / Sensory perception of sweet, bitter, and umami (glutamate) taste / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / G alpha (z) signalling events / ADP signalling through P2Y purinoceptor 1 / cellular response to catecholamine stimulus / ADORA2B mediated anti-inflammatory cytokines production / G beta:gamma signalling through PI3Kgamma / adenylate cyclase-activating dopamine receptor signaling pathway / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / G-protein beta-subunit binding / cellular response to prostaglandin E stimulus / heterotrimeric G-protein complex / Inactivation, recovery and regulation of the phototransduction cascade / G alpha (12/13) signalling events / extracellular vesicle / sensory perception of taste / Thrombin signalling through proteinase activated receptors (PARs) / signaling receptor complex adaptor activity / retina development in camera-type eye / GTPase binding / Ca2+ pathway / fibroblast proliferation / Interleukin-4 and Interleukin-13 signaling / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / G alpha (i) signalling events / G alpha (s) signalling events / phospholipase C-activating G protein-coupled receptor signaling pathway / perikaryon / G alpha (q) signalling events / Ras protein signal transduction / Extra-nuclear estrogen signaling / positive regulation of ERK1 and ERK2 cascade / cell population proliferation / endosome / neuron projection / G protein-coupled receptor signaling pathway / axon / negative regulation of cell population proliferation / lysosomal membrane / GTPase activity / synapse / dendrite / protein-containing complex binding / endoplasmic reticulum / Golgi apparatus / signal transduction / extracellular exosome / membrane / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Mu opioid receptor / Opioid receptor / G-protein, gamma subunit / G-protein gamma subunit domain profile. / G-protein gamma-like domain / G-protein gamma-like domain superfamily / GGL domain / G protein gamma subunit-like motifs / GGL domain / G protein beta WD-40 repeat protein ...Mu opioid receptor / Opioid receptor / G-protein, gamma subunit / G-protein gamma subunit domain profile. / G-protein gamma-like domain / G-protein gamma-like domain superfamily / GGL domain / G protein gamma subunit-like motifs / GGL domain / G protein beta WD-40 repeat protein / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / 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) / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily
Similarity search - Domain/homology
Mu-type opioid receptor / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
Similarity search - Component
Biological speciesHomo sapiens (human) / Oplophorus gracilirostris (crustacean) / 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-
UpdateDec 24, 2025-
Current statusDec 24, 2025Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_66205.png

Downloads & links

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Map

FileDownload / File: emd_66205.map.gz / Format: CCP4 / Size: 42.9 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.93 Å/pix.
x 224 pix.
= 208.32 Å		0.93 Å/pix.
x 224 pix.
= 208.32 Å		0.93 Å/pix.
x 224 pix.
= 208.32 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.93 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.005
Minimum - Maximum-0.023929298 - 0.04379716
Average (Standard dev.)0.0000012071813 (±0.0011999487)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions224224224
Spacing224224224
CellA=B=C: 208.32 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_66205_half_map_1.map
Projections & Slices
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Density Histograms

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Half map: #1

Fileemd_66205_half_map_2.map
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Sample components

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Entire : Complex of DAMGO bound MOR-Gz protein

EntireName: Complex of DAMGO bound MOR-Gz protein
Components
  • Complex: Complex of DAMGO bound MOR-Gz protein
    • Protein or peptide: Engineered guanine nucleotide-binding protein G(z) subunit alpha
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Protein or peptide: Mu-type opioid receptor,LgBiT
  • Protein or peptide: DAMGO
  • Ligand: water

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

SupramoleculeName: Complex of DAMGO bound MOR-Gz protein / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Engineered guanine nucleotide-binding protein G(z) subunit alpha

MacromoleculeName: Engineered guanine nucleotide-binding protein G(z) subunit alpha
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 40.699516 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MGCTLSAEDK AAVERSKMID RNLREDGEKQ RREIKLLLLG TSNSGKNTIV KQMKIIHSGG FNLEACKEYK PLIIYNAIDS LTRIIRALA ALRIDFHNPD RAYDAVQLFA LTGPAESKGE ITPELLGVMR RLWADPGAQA CFSRSSEYHL EDNAAYYLND L ERIAAADY ...String:
MGCTLSAEDK AAVERSKMID RNLREDGEKQ RREIKLLLLG TSNSGKNTIV KQMKIIHSGG FNLEACKEYK PLIIYNAIDS LTRIIRALA ALRIDFHNPD RAYDAVQLFA LTGPAESKGE ITPELLGVMR RLWADPGAQA CFSRSSEYHL EDNAAYYLND L ERIAAADY IPTVEDILRS RDMTTGIVEN KFTFKELTFK MVDVGAQRSE RKKWIHCFEG VTAIIFCVEL SGYDLKLYED NQ TSRMAAS LKLFDSICNN KWFIDTSLIL FLNKKDLLAE KIRRIPLTIC FPEYKGQNTY EEAAVYIQRQ FEDLNRNKET KEI YSHFTC STDTSNIQFV FDAVTDVIIQ NNLKYIGLC

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Macromolecule #2: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1

MacromoleculeName: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 40.039648 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: GPGSSGSELD QLRQEAEQLK NQIRDARKAC ADATLSQITN NIDPVGRIQM RTRRTLRGHL AKIYAMHWGT DSRLLVSASQ DGKLIIWDS YTTNKVHAIP LRSSWVMTCA YAPSGNYVAC GGLDNICSIY NLKTREGNVR VSRELAGHTG YLSCCRFLDD N QIVTSSGD ...String:
GPGSSGSELD QLRQEAEQLK NQIRDARKAC ADATLSQITN NIDPVGRIQM RTRRTLRGHL AKIYAMHWGT DSRLLVSASQ DGKLIIWDS YTTNKVHAIP LRSSWVMTCA YAPSGNYVAC GGLDNICSIY NLKTREGNVR VSRELAGHTG YLSCCRFLDD N QIVTSSGD TTCALWDIET GQQTTTFTGH TGDVMSLSLA PDTRLFVSGA CDASAKLWDV REGMCRQTFT GHESDINAIC FF PNGNAFA TGSDDATCRL FDLRADQELM TYSHDNIICG ITSVSFSKSG RLLLAGYDDF NCNVWDALKA DRAGVLAGHD NRV SCLGVT DDGMAVATGS WDSFLKIWNG SSGGGGSGGG GSSGVSGWRL FKKIS

UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1

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Macromolecule #3: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2

MacromoleculeName: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 7.861143 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString:
MASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFCAI L

UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2

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Macromolecule #4: Mu-type opioid receptor,LgBiT

MacromoleculeName: Mu-type opioid receptor,LgBiT / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Oplophorus gracilirostris (crustacean)
Molecular weightTheoretical: 64.018785 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: DYKDDDDKGP GNISDCSDPL APASCSPAPS PGSWLNLSHV DGNQSDPCGP NRTGLGGSHS LCPQTGSPSM VTAITIMALY SIVCVVGLF GNFLVMYVIV RYTKMKTATN IYIFNLALAD ALATSTLPFQ SVNYLMGTWP FGNILCKIVI SIDYYNMFTS I FTLCTMSV ...String:
DYKDDDDKGP GNISDCSDPL APASCSPAPS PGSWLNLSHV DGNQSDPCGP NRTGLGGSHS LCPQTGSPSM VTAITIMALY SIVCVVGLF GNFLVMYVIV RYTKMKTATN IYIFNLALAD ALATSTLPFQ SVNYLMGTWP FGNILCKIVI SIDYYNMFTS I FTLCTMSV DRYIAVCHPV KALDFRTPRN AKIVNVCNWI LSSAIGLPVM FMATTKYRQG SIDCTLTFSH PTWYWENLLK IC VFIFAFI MPVLIITVCY GLMILRLKSV RMLSGSKEKD RNLRRITRMV LVVVAVFIVC WTPIHIYVII KALITIPETT FQT VSWHFC IALGYTNSCL NPVLYAFLDE NFKRCFREFC IPTSSTIEQQ NSARIRQNTR EHPSTANTVD RTNHQLENLE AETA PLPGG SSGVFTLEDF VGDWEQTAAY NLDQVLEQGG VSSLLQNLAV SVTPIQRIVR SGENALKIDI HVIIPYEGLS ADQMA QIEE VFKVVYPVDD HHFKVILPYG TLVIDGVTPN MLNYFGRPYE GIAVFDGKKI TVTGTLWNGN KIIDERLITP DGSMLF RVT INSGGSLEVL FQ

UniProtKB: Mu-type opioid receptor

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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: 1 / 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: 136606
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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