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- EMDB-44924: Structure of GGCX-BGP-menaquinone-4 epoxide complex -

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Basic information

Entry
Database: EMDB / ID: EMD-44924
TitleStructure of GGCX-BGP-menaquinone-4 epoxide complex
Map data
Sample
  • Complex: GGCX-BGP-menaquinone-4 epoxide complex
    • Protein or peptide: Vitamin K-dependent gamma-carboxylase
    • Protein or peptide: Osteocalcin
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: CHOLESTEROL
  • Ligand: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate
  • Ligand: (1aR,7aS)-1a-methyl-7a-[(2E,6E,10E)-3,7,11,15-tetramethylhexadeca-2,6,10,14-tetraen-1-yl]-1a,7a-dihydronaphtho[2,3-b]oxirene-2,7-dione
Keywordsvitamin K cycle / MEMBRANE PROTEIN / LYASE-SUBSTRATE complex
Function / homology
Function and homology information


structural constituent of bone / hydroxyapatite binding / peptidyl-glutamate 4-carboxylase / gamma-glutamyl carboxylase activity / negative regulation of bone development / response to macrophage colony-stimulating factor / Defective gamma-carboxylation of F9 / vitamin binding / vitamin K metabolic process / regulation of testosterone biosynthetic process ...structural constituent of bone / hydroxyapatite binding / peptidyl-glutamate 4-carboxylase / gamma-glutamyl carboxylase activity / negative regulation of bone development / response to macrophage colony-stimulating factor / Defective gamma-carboxylation of F9 / vitamin binding / vitamin K metabolic process / regulation of testosterone biosynthetic process / response to gravity / response to vitamin K / regulation of osteoclast differentiation / cellular response to zinc ion starvation / type B pancreatic cell proliferation / cellular response to vitamin D / regulation of bone mineralization / response to vitamin D / regulation of bone resorption / osteoblast development / response to hydroxyisoflavone / positive regulation of neurotransmitter secretion / response to zinc ion / bone mineralization / RUNX2 regulates osteoblast differentiation / response to testosterone / Transport of gamma-carboxylated protein precursors from the endoplasmic reticulum to the Golgi apparatus / Gamma-carboxylation of protein precursors / Removal of aminoterminal propeptides from gamma-carboxylated proteins / response to glucocorticoid / response to mechanical stimulus / regulation of cellular response to insulin stimulus / protein maturation / response to activity / skeletal system development / stem cell differentiation / brain development / cellular response to growth factor stimulus / protein modification process / hormone activity / bone development / Golgi lumen / cognition / cellular response to insulin stimulus / response to estrogen / osteoblast differentiation / blood coagulation / glucose homeostasis / vesicle / perikaryon / response to ethanol / learning or memory / cell adhesion / endoplasmic reticulum lumen / response to xenobiotic stimulus / dendrite / calcium ion binding / endoplasmic reticulum membrane / structural molecule activity / extracellular space / extracellular region / membrane / cytoplasm
Similarity search - Function
Osteocalcin/matrix Gla protein / Osteocalcin / Vitamin K-dependent gamma-carboxylase / HTTM / : / : / HTTM domain / Vitamin K-dependent gamma-carboxylase, lumenal domain / Horizontally Transferred TransMembrane Domain / RmlC-like cupin domain superfamily ...Osteocalcin/matrix Gla protein / Osteocalcin / 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: 3.06 Å
AuthorsWang R / Qi X
Funding support United States, 1 items
OrganizationGrant numberCountry
Cancer Prevention and Research Institute of Texas (CPRIT)RR230054 United States
CitationJournal: Nature / Year: 2025
Title: Structure and mechanism of vitamin-K-dependent γ-glutamyl carboxylase.
Authors: Rong Wang / Baozhi Chen / Nadia Elghobashi-Meinhardt / Jian-Ke Tie / Alyssa Ayala / Ning Zhou / Xiaofeng Qi /
Abstract: γ-Glutamyl carboxylase (GGCX) is the sole identified enzyme that uses vitamin K (VK) as a cofactor in humans. This protein catalyses the oxidation of VK hydroquinone to convert specific glutamate ...γ-Glutamyl carboxylase (GGCX) is the sole identified enzyme that uses vitamin K (VK) as a cofactor in humans. This protein catalyses the oxidation of VK hydroquinone to convert specific glutamate residues to γ-carboxyglutamate residues in VK-dependent proteins (VDPs), which are involved in various essential biological processes and diseases. However, the working mechanism of GGCX remains unclear. Here we report three cryogenic electron microscopy structures of human GGCX: in the apo state, bound to osteocalcin (a VDP) and bound to VK. The propeptide of the VDP binds to the lumenal domain of GGCX, which stabilizes transmembrane helices 6 and 7 of GGCX to create the VK-binding pocket. After binding of VK, residue Lys218 in GGCX mediates the oxidation of VK hydroxyquinone, which leads to the deprotonation of glutamate residues and the construction of γ-carboxyglutamate residues. Our structural observations and results from binding and cell biological assays and molecular dynamics simulations show that a cholesterol molecule interacts with the transmembrane helices of GGCX to regulate its protein levels in cells. Together, these results establish a link between cholesterol metabolism and VK-dependent pathways.
History
DepositionMay 17, 2024-
Header (metadata) releaseJan 29, 2025-
Map releaseJan 29, 2025-
UpdateMar 26, 2025-
Current statusMar 26, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_44924.png

Downloads & links

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Map

FileDownload / File: emd_44924.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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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.83 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.311
Minimum - Maximum-1.1815139 - 2.4728048
Average (Standard dev.)0.0003372034 (±0.05012964)
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: #2

Fileemd_44924_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: #1

Fileemd_44924_half_map_2.map
Projections & Slices
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Histogram

Histogram (log scale)

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Sample components

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Entire : GGCX-BGP-menaquinone-4 epoxide complex

EntireName: GGCX-BGP-menaquinone-4 epoxide complex
Components
  • Complex: GGCX-BGP-menaquinone-4 epoxide complex
    • Protein or peptide: Vitamin K-dependent gamma-carboxylase
    • Protein or peptide: Osteocalcin
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: CHOLESTEROL
  • Ligand: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate
  • Ligand: (1aR,7aS)-1a-methyl-7a-[(2E,6E,10E)-3,7,11,15-tetramethylhexadeca-2,6,10,14-tetraen-1-yl]-1a,7a-dihydronaphtho[2,3-b]oxirene-2,7-dione

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Supramolecule #1: GGCX-BGP-menaquinone-4 epoxide complex

SupramoleculeName: GGCX-BGP-menaquinone-4 epoxide 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: 88.652609 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 DPVHSEFDYK DDDDK

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: 11.804439 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
MRALTLLALL ALAALCIAGQ AGAKPSGAES SKGAAFVSKQ EGSEVVKRPR RYLYQWLGAP VPYPDPLEPR REVCELNPDC DELADHIGF QEAYRRFYGP VHHHHHH

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: (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: 6 / 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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Macromolecule #7: (1aR,7aS)-1a-methyl-7a-[(2E,6E,10E)-3,7,11,15-tetramethylhexadeca...

MacromoleculeName: (1aR,7aS)-1a-methyl-7a-[(2E,6E,10E)-3,7,11,15-tetramethylhexadeca-2,6,10,14-tetraen-1-yl]-1a,7a-dihydronaphtho[2,3-b]oxirene-2,7-dione
type: ligand / ID: 7 / Number of copies: 1 / Formula: A1AT1
Molecular weightTheoretical: 460.648 Da

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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

MicroscopeFEI TITAN 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

Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.06 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 195408
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE

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