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- EMDB-77079: Structure of GGCX-BGP-Anisindione complex -

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Basic information

Entry
Database: EMDB / ID: EMD-77079
TitleStructure of GGCX-BGP-Anisindione complex
Map data
Sample
  • Complex: GGCX-BGP-Anisindione complex
    • Protein or peptide: Vitamin K-dependent gamma-carboxylase
    • Protein or peptide: Osteocalcin
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: CHOLESTEROL
  • Ligand: anisindione
  • Ligand: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate
Keywordsvitamin K / MEMBRANE PROTEIN
Function / homology
Function and homology information


response to hydroxyisoflavone / hydroxyapatite binding / structural constituent of bone / type B pancreatic cell proliferation / cellular response to zinc ion starvation / peptidyl-glutamate 4-carboxylase / gamma-glutamyl carboxylase activity / negative regulation of testosterone biosynthetic process / peptidyl-glutamic acid carboxylation / negative regulation of bone development ...response to hydroxyisoflavone / hydroxyapatite binding / structural constituent of bone / type B pancreatic cell proliferation / cellular response to zinc ion starvation / peptidyl-glutamate 4-carboxylase / gamma-glutamyl carboxylase activity / negative regulation of testosterone biosynthetic process / peptidyl-glutamic acid carboxylation / negative regulation of bone development / response to macrophage colony-stimulating factor / regulation of testosterone biosynthetic process / vitamin binding / vitamin K metabolic process / Defective gamma-carboxylation of F9 / positive regulation of neurotransmitter secretion / response to vitamin K / regulation of osteoclast differentiation / cellular response to vitamin D / regulation of bone mineralization / response to vitamin D / non-collagenous component of basement membrane / negative regulation of neurotransmitter secretion / regulation of bone resorption / bone mineralization / response to zinc ion / RUNX2 regulates osteoblast differentiation / response to gravity / response to testosterone / skeletal system development / Transport of gamma-carboxylated protein precursors from the endoplasmic reticulum to the Golgi apparatus / response to mechanical stimulus / Gamma-carboxylation of protein precursors / Removal of aminoterminal propeptides from gamma-carboxylated proteins / stem cell differentiation / regulation of cellular response to insulin stimulus / hormone activity / response to glucocorticoid / response to activity / protein modification process / brain development / bone development / blood coagulation / osteoblast differentiation / response to estrogen / Golgi lumen / cellular response to growth factor stimulus / cognition / protein maturation / cellular response to insulin stimulus / glucose homeostasis / cell adhesion / vesicle / response to ethanol / perikaryon / learning or memory / response to xenobiotic stimulus / endoplasmic reticulum lumen / calcium ion binding / dendrite / endoplasmic reticulum membrane / structural molecule activity / extracellular region / membrane / cytoplasm
Similarity search - Function
Osteocalcin / Osteocalcin/matrix Gla protein / : / Osteocalcin, C-terminal domain / Vitamin K-dependent gamma-carboxylase / HTTM / : / : / HTTM domain / Vitamin K-dependent gamma-carboxylase, lumenal domain ...Osteocalcin / Osteocalcin/matrix Gla protein / : / Osteocalcin, C-terminal domain / Vitamin K-dependent gamma-carboxylase / HTTM / : / : / HTTM domain / Vitamin K-dependent gamma-carboxylase, lumenal domain / Horizontally Transferred TransMembrane Domain / RmlC-like cupin domain superfamily / Gamma-carboxyglutamic acid-rich (GLA) domain / Gamma-carboxyglutamic acid-rich (GLA) domain superfamily / Vitamin K-dependent carboxylation domain. / Gla domain profile. / Domain containing Gla (gamma-carboxyglutamate) residues. / RmlC-like jelly roll fold
Similarity search - Domain/homology
Osteocalcin / Vitamin K-dependent gamma-carboxylase
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.68 Å
AuthorsWang R / Qi X / Zhou N
Funding support United States, 1 items
OrganizationGrant numberCountry
Cancer Prevention and Research Institute of Texas (CPRIT)RR230054 United States
CitationJournal: Structure / Year: 2026
Title: γ-glutamyl carboxylase inhibition by Anisindione.
Authors: Ning Zhou / Rong Wang / Baozhi Chen / Jie Li / Jian-Ke Tie / Fangyu Liu / Xiaofeng Qi /
Abstract: The maturation of key coagulation factors requires γ-carboxylation catalyzed by γ-glutamyl carboxylase (GGCX), in which vitamin K hydroquinone (VKH) is oxidized to vitamin K epoxide (VKO) and ...The maturation of key coagulation factors requires γ-carboxylation catalyzed by γ-glutamyl carboxylase (GGCX), in which vitamin K hydroquinone (VKH) is oxidized to vitamin K epoxide (VKO) and recycled by vitamin K epoxide reductase (VKORC1). Clinically, vitamin K antagonists (VKAs) inhibit VKORC1 but are thought not to target GGCX. Here, we demonstrate that a member of VKA, anisindione and its analogs can dock within the VK-binding pocket of GGCX. Importantly, both in vitro and cell-based γ-carboxylation assays showed that anisindione inhibits GGCX activity. Furthermore, our cryo-electron microscopy structure of the GGCX-BGP (bone Gla protein or osteocalcin)-anisindione complex reveals that anisindione directly occupies the VK-binding pocket of GGCX, consistent with competitive inhibition with VK. These results establish anisindione as a structural prototype for direct GGCX inhibition and provide a structural framework for developing anticoagulants beyond VKORC1.
History
DepositionMay 7, 2026-
Header (metadata) releaseSep 2, 2026-
Map releaseSep 2, 2026-
UpdateOct 14, 2026-
Current statusOct 14, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_77079.png

Downloads & links

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Map

FileDownload / File: emd_77079.map.gz / Format: CCP4 / Size: 83.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 280 pix.
= 232.4 Å		0.83 Å/pix.
x 280 pix.
= 232.4 Å		0.83 Å/pix.
x 280 pix.
= 232.4 Å

Surface

Projections

Slices (1/3)

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Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.83 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.491
Minimum - Maximum-4.014852 - 5.558331
Average (Standard dev.)-0.0015572156 (±0.115989216)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions280280280
Spacing280280280
CellA=B=C: 232.4 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_77079_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_77079_half_map_2.map
Projections & Slices
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Sample components

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Entire : GGCX-BGP-Anisindione complex

EntireName: GGCX-BGP-Anisindione complex
Components
  • Complex: GGCX-BGP-Anisindione complex
    • Protein or peptide: Vitamin K-dependent gamma-carboxylase
    • Protein or peptide: Osteocalcin
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: CHOLESTEROL
  • Ligand: anisindione
  • Ligand: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate

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Supramolecule #1: GGCX-BGP-Anisindione complex

SupramoleculeName: GGCX-BGP-Anisindione complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Vitamin K-dependent gamma-carboxylase

MacromoleculeName: Vitamin K-dependent gamma-carboxylase / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO / EC number: peptidyl-glutamate 4-carboxylase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 87.655641 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MAVSAGSART SPSSDKVQKD KAELISGPRQ DSRIGKLLGF EWTDLSSWRR LVTLLNRPTD PASLAVFRFL FGFLMVLDIP QERGLSSLD RKYLDGLDVC RFPLLDALRP LPLDWMYLVY TIMFLGALGM MLGLCYRISC VLFLLPYWYV FLLDKTSWNN H SYLYGLLA ...String:
MAVSAGSART SPSSDKVQKD KAELISGPRQ DSRIGKLLGF EWTDLSSWRR LVTLLNRPTD PASLAVFRFL FGFLMVLDIP QERGLSSLD RKYLDGLDVC RFPLLDALRP LPLDWMYLVY TIMFLGALGM MLGLCYRISC VLFLLPYWYV FLLDKTSWNN H SYLYGLLA FQLTFMDANH YWSVDGLLNA HRRNAHVPLW NYAVLRGQIF IVYFIAGVKK LDADWVEGYS MEYLSRHWLF SP FKLLLSE ELTSLLVVHW GGLLLDLSAG FLLFFDVSRS IGLFFVSYFH CMNSQLFSIG MFSYVMLASS PLFCSPEWPR KLV SYCPRR LQQLLPLKAA PQPSVSCVYK RSRGKSGQKP GLRHQLGAAF TLLYLLEQLF LPYSHFLTQG YNNWTNGLYG YSWD MMVHS RSHQHVKITY RDGRTGELGY LNPGVFTQSR RWKDHADMLK QYATCLSRLL PKYNVTEPQI YFDIWVSIND RFQQR IFDP RVDIVQAAWS PFQRTSWVQP LLMDLSPWRA KLQEIKSSLD NHTEVVFIAD FPGLHLENFV SEDLGNTSIQ LLQGEV TVE LVAEQKNQTL REGEKMQLPA GEYHKVYTTS PSPSCYMYVY VNTTELALEQ DLAYLQELKE KVENGSETGP LPPELQP LL EGEVKGGPEP TPLVQTFLRR QQRLQEIERR RNTPFHERFF RFLLRKLYVF RRSFLMTCIS LRNLILGRPS LEQLAQEV T YANLRPFEAV GELNPSNTDS SHSNPPESNP DPVHSEF

UniProtKB: Vitamin K-dependent gamma-carboxylase

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Macromolecule #2: Osteocalcin

MacromoleculeName: Osteocalcin / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 10.975558 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
MRALTLLALL ALAALCIAGQ AGAKPSGAES SKGAAFVSKQ EGSEVVKRPR RYLYQWLGAP VPYPDPLEPR REVCELNPDC DELADHIGF QEAYRRFYGP V

UniProtKB: Osteocalcin

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Macromolecule #4: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 4 / Number of copies: 2 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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Macromolecule #5: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 5 / Number of copies: 1 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL

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Macromolecule #6: anisindione

MacromoleculeName: anisindione / type: ligand / ID: 6 / Number of copies: 1 / Formula: A1AT0
Molecular weightTheoretical: 252.265 Da

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Macromolecule #7: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(tri...

MacromoleculeName: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate
type: ligand / ID: 7 / Number of copies: 1 / Formula: POV
Molecular weightTheoretical: 760.076 Da
Chemical component information

ChemComp-POV:
(2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate / phospholipid*YM

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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: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 60.0 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: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: NONE
Startup modelType of model: OTHER
Final reconstructionNumber classes used: 757035 / Resolution.type: BY AUTHOR / Resolution: 2.68 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 3207368
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE

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