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- EMDB-62822: cryo-EM structure of Vitamin K-dependent gamma-carboxylase comple... -

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Basic information

Entry
Database: EMDB / ID: EMD-62822
Titlecryo-EM structure of Vitamin K-dependent gamma-carboxylase complexed with Vitamin K1 2,3-epoxide
Map data
Sample
  • Complex: Vitamin K-dependent gamma-carboxylase complexed with Vitamin K1 2,3-epoxide
    • Protein or peptide: Vitamin K-dependent gamma-carboxylase
    • Protein or peptide: Vitamin K-dependent protein S
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: (1~{a}~{R},7~{a}~{S})-7~{a}-methyl-1~{a}-[(~{E},7~{R},11~{R})-3,7,11,15-tetramethylhexadec-2-enyl]naphtho[2,3-b]oxirene-2,7-dione
  • Ligand: CHOLESTEROL
  • Ligand: 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine
  • Ligand: CHOLESTEROL HEMISUCCINATE
  • Ligand: BICARBONATE ION
KeywordsMEMBRANE PROTEIN
Function / homology
Function and homology information


peptidyl-glutamate 4-carboxylase / gamma-glutamyl carboxylase activity / negative regulation of testosterone biosynthetic process / negative regulation of bone development / Defective gamma-carboxylation of F9 / vitamin binding / vitamin K metabolic process / negative regulation of neurotransmitter secretion / type B pancreatic cell proliferation / endopeptidase inhibitor activity ...peptidyl-glutamate 4-carboxylase / gamma-glutamyl carboxylase activity / negative regulation of testosterone biosynthetic process / negative regulation of bone development / Defective gamma-carboxylation of F9 / vitamin binding / vitamin K metabolic process / negative regulation of neurotransmitter secretion / type B pancreatic cell proliferation / endopeptidase inhibitor activity / 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 / fibrinolysis / : / platelet alpha granule lumen / Regulation of Complement cascade / protein modification process / Cell surface interactions at the vascular wall / protein maturation / Golgi lumen / cellular response to insulin stimulus / blood coagulation / Platelet degranulation / glucose homeostasis / blood microparticle / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / endoplasmic reticulum lumen / Golgi membrane / calcium ion binding / endoplasmic reticulum membrane / : / extracellular exosome / extracellular region / membrane / plasma membrane
Similarity search - Function
: / Vitamin K-dependent gamma-carboxylase / HTTM / : / : / HTTM domain / Vitamin K-dependent gamma-carboxylase, lumenal domain / Horizontally Transferred TransMembrane Domain / Laminin G domain / EGF-like, conserved site ...: / Vitamin K-dependent gamma-carboxylase / HTTM / : / : / HTTM domain / Vitamin K-dependent gamma-carboxylase, lumenal domain / Horizontally Transferred TransMembrane Domain / Laminin G domain / EGF-like, conserved site / Human growth factor-like EGF / Laminin G domain / Laminin G domain profile. / Laminin G domain / Laminin G domain / : / Calcium-binding EGF domain / Coagulation factor-like, Gla domain superfamily / Coagulation Factor Xa inhibitory site / RmlC-like cupin domain superfamily / EGF-type aspartate/asparagine hydroxylation site / EGF-like calcium-binding, conserved site / Calcium-binding EGF-like domain signature. / Aspartic acid and asparagine hydroxylation site. / EGF-like calcium-binding domain / Calcium-binding EGF-like domain / Vitamin K-dependent carboxylation/gamma-carboxyglutamic (GLA) domain / 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. / Epidermal growth factor-like domain. / EGF-like domain profile. / Growth factor receptor cysteine-rich domain superfamily / EGF-like domain signature 1. / EGF-like domain signature 2. / EGF-like domain / RmlC-like jelly roll fold / Concanavalin A-like lectin/glucanase domain superfamily
Similarity search - Domain/homology
Vitamin K-dependent protein S / Vitamin K-dependent gamma-carboxylase
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.04 Å
AuthorsYao D / Wu K / Lan P
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: Nat Commun / Year: 2025
Title: Structural insight into bicarbonate-mediated carboxylation by human vitamin K-dependent carboxylase.
Authors: Ke Wu / Zheng Wang / Deqiang Yao / Shaobai Li / Xiaozhu Wang / Yuanyuan Zhang / Mi Cao / Yafeng Shen / Shunpeng Xing / Jian Wu / Ming Lei / Pengfei Lan /
Abstract: Vitamin K-dependent (VKD) carboxylation, mediated by γ-glutamyl carboxylase (GGCX), is essential for the maturation of VKD proteins involved in critical physiological processes such as blood ...Vitamin K-dependent (VKD) carboxylation, mediated by γ-glutamyl carboxylase (GGCX), is essential for the maturation of VKD proteins involved in critical physiological processes such as blood clotting, vascular calcification and bone metabolism. Here, we present cryo-electron microscopic structures of human GGCX alone and in complex with VKD proteins, vitamin K, and inhibitor anisindione. GGCX specifically recognizes diverse VKD substrates through high-affinity propeptide binding, while substrates like osteocalcin utilize a secondary exosite to enhance interaction. GGCX employs a conserved dipeptide anchoring mechanism that ensures processive carboxylation of glutamate residues. GGCX undergoes allosteric conformational changes that enable coordinated binding of vitamin K and glutamate substrates, facilitating the catalytic process. Additionally, we reveal a bicarbonate-mediated CO₂ capture mechanism that is conserved across bacterial and eukaryotic species, suggesting that this strategy for CO₂ utilization is both ancient and universal. Our findings lay the foundation for developing targeted anticoagulant drugs and innovative enzymatic CO₂ fixation strategies.
History
DepositionDec 22, 2024-
Header (metadata) releaseOct 22, 2025-
Map releaseOct 22, 2025-
UpdateMay 6, 2026-
Current statusMay 6, 2026Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_62822.png

Downloads & links

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Map

FileDownload / File: emd_62822.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.86 Å/pix.
x 256 pix.
= 220.16 Å		0.86 Å/pix.
x 256 pix.
= 220.16 Å		0.86 Å/pix.
x 256 pix.
= 220.16 Å

Surface

Projections

Slices (1/3)

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Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.86 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.3
Minimum - Maximum-3.3568726 - 4.662882
Average (Standard dev.)0.00066087605 (±0.096215785)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 220.16 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_62822_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_62822_half_map_2.map
Projections & Slices
AxesZYX

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Histogram (log scale)

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Sample components

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Entire : Vitamin K-dependent gamma-carboxylase complexed with Vitamin K1 2...

EntireName: Vitamin K-dependent gamma-carboxylase complexed with Vitamin K1 2,3-epoxide
Components
  • Complex: Vitamin K-dependent gamma-carboxylase complexed with Vitamin K1 2,3-epoxide
    • Protein or peptide: Vitamin K-dependent gamma-carboxylase
    • Protein or peptide: Vitamin K-dependent protein S
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: (1~{a}~{R},7~{a}~{S})-7~{a}-methyl-1~{a}-[(~{E},7~{R},11~{R})-3,7,11,15-tetramethylhexadec-2-enyl]naphtho[2,3-b]oxirene-2,7-dione
  • Ligand: CHOLESTEROL
  • Ligand: 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine
  • Ligand: CHOLESTEROL HEMISUCCINATE
  • Ligand: BICARBONATE ION

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Supramolecule #1: Vitamin K-dependent gamma-carboxylase complexed with Vitamin K1 2...

SupramoleculeName: Vitamin K-dependent gamma-carboxylase complexed with Vitamin K1 2,3-epoxide
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: 81.404992 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: SRIGKLLGFE WTDLSSWRRL VTLLNRPTDP ASLAVFRFLF GFLMVLDIPQ ERGLSSLDRK YLDGLDVCRF PLLDALRPLP LDWMYLVYT IMFLGALGMM LGLCYRISCV LFLLPYWYVF LLDKTSWNNH SYLYGLLAFQ LTFMDANHYW SVDGLLNAHR R NAHVPLWN ...String:
SRIGKLLGFE WTDLSSWRRL VTLLNRPTDP ASLAVFRFLF GFLMVLDIPQ ERGLSSLDRK YLDGLDVCRF PLLDALRPLP LDWMYLVYT IMFLGALGMM LGLCYRISCV LFLLPYWYVF LLDKTSWNNH SYLYGLLAFQ LTFMDANHYW SVDGLLNAHR R NAHVPLWN YAVLRGQIFI VYFIAGVKKL DADWVEGYSM EYLSRHWLFS PFKLLLSEEL TSLLVVHWGG LLLDLSAGFL LF FDVSRSI GLFFVSYFHC MNSQLFSIGM FSYVMLASSP LFCSPEWPRK LVSYCPRRLQ QLLPLKAAPQ PSVSCVYKRS RGK SGQKPG LRHQLGAAFT LLYLLEQLFL PYSHFLTQGY NNWTNGLYGY SWDMMVHSRS HQHVKITYRD GRTGELGYLN PGVF TQSRR WKDHADMLKQ YATCLSRLLP KYNVTEPQIY FDIWVSINDR FQQRIFDPRV DIVQAAWSPF QRTSWVQPLL MDLSP WRAK LQEIKSSLDN HTEVVFIADF PGLHLENFVS EDLGNTSIQL LQGEVTVELV AEQKNQTLRE GEKMQLPAGE YHKVYT TSP SPSCYMYVYV NTTELALEQD LAYLQELKEK VENGSETGPL PPELQPLLEG EVKGGPEPTP LVQTFLRRQQ RLQEIER RR NTPFHERFFR FLLRKLYVFR RSFLMTCISL RNLILGRPSL EQLAQEVTYA NLRPFE

UniProtKB: Vitamin K-dependent gamma-carboxylase

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Macromolecule #2: Vitamin K-dependent protein S

MacromoleculeName: Vitamin K-dependent protein S / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 3.077474 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
ANFLSKQQAS QVLVRKRRAN SALEEEV

UniProtKB: Vitamin K-dependent protein S

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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: 1 / 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: (1~{a}~{R},7~{a}~{S})-7~{a}-methyl-1~{a}-[(~{E},7~{R},11~{R})-3,7...

MacromoleculeName: (1~{a}~{R},7~{a}~{S})-7~{a}-methyl-1~{a}-[(~{E},7~{R},11~{R})-3,7,11,15-tetramethylhexadec-2-enyl]naphtho[2,3-b]oxirene-2,7-dione
type: ligand / ID: 5 / Number of copies: 1 / Formula: A1EIL
Molecular weightTheoretical: 466.695 Da

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Macromolecule #6: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 6 / Number of copies: 1 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL

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Macromolecule #7: 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine

MacromoleculeName: 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine / type: ligand / ID: 7 / Number of copies: 3 / Formula: PEE
Molecular weightTheoretical: 744.034 Da
Chemical component information

ChemComp-PEE:
1,2-dioleoyl-sn-glycero-3-phosphoethanolamine / DOPE, phospholipid*YM

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Macromolecule #8: CHOLESTEROL HEMISUCCINATE

MacromoleculeName: CHOLESTEROL HEMISUCCINATE / type: ligand / ID: 8 / Number of copies: 1 / Formula: Y01
Molecular weightTheoretical: 486.726 Da
Chemical component information

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

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Macromolecule #9: BICARBONATE ION

MacromoleculeName: BICARBONATE ION / type: ligand / ID: 9 / Number of copies: 1 / Formula: BCT
Molecular weightTheoretical: 61.017 Da
Chemical component information

ChemComp-BCT:
BICARBONATE ION

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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/PHILIPS CM300FEG/T
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.7 µm / Nominal defocus min: 0.9 µm

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.04 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 319391
Initial angle assignmentType: RANDOM ASSIGNMENT
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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