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- PDB-9l20: cryo-EM structure of Vitamin K-dependent gamma-carboxylase comple... -

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Basic information

Entry
Database: PDB / ID: 9l20
Titlecryo-EM structure of Vitamin K-dependent gamma-carboxylase complexed with anisindione
Components(Vitamin K-dependent ...) x 2
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
: / BICARBONATE ION / CHOLESTEROL / 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine / CHOLESTEROL HEMISUCCINATE / Vitamin K-dependent protein S / Vitamin K-dependent gamma-carboxylase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.82 Å
AuthorsYao, D. / Wu, K. / Lan, P.
Funding support China, 1items
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 16, 2024Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Oct 22, 2025Provider: repository / Type: Initial release
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Vitamin K-dependent gamma-carboxylase
B: Vitamin K-dependent protein S
hetero molecules


Theoretical massNumber of molelcules
Total (without water)88,88612
Polymers84,3972
Non-polymers4,48910
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Vitamin K-dependent ... , 2 types, 2 molecules AB

#1: Protein Vitamin K-dependent gamma-carboxylase / Gamma-glutamyl carboxylase / Peptidyl-glutamate 4-carboxylase / Vitamin K gamma glutamyl carboxylase


Mass: 81404.992 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GGCX, GC / Production host: Homo sapiens (human)
References: UniProt: P38435, peptidyl-glutamate 4-carboxylase
#2: Protein/peptide Vitamin K-dependent protein S


Mass: 2992.413 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PROS1, PROS / Production host: Homo sapiens (human) / References: UniProt: P07225

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Sugars , 2 types, 3 molecules

#3: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE
#4: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Non-polymers , 5 types, 7 molecules

#5: Chemical ChemComp-A1AT0 / anisindione / 2-(4-methoxyphenyl)-1H-indene-1,3(2H)-dione


Mass: 252.265 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H12O3 / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H46O
#7: Chemical ChemComp-PEE / 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine / DOPE


Mass: 744.034 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C41H78NO8P / Comment: DOPE, phospholipid*YM
#8: Chemical ChemComp-Y01 / CHOLESTEROL HEMISUCCINATE


Mass: 486.726 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C31H50O4
#9: Chemical ChemComp-BCT / BICARBONATE ION


Mass: 61.017 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: CHO3

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Details

Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Vitamin K-dependent gamma-carboxylase complexed with anisindione
Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

MicroscopyModel: FEI/PHILIPS CM300FEG/T
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1700 nm / Nominal defocus min: 900 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM software
IDNameVersionCategory
1RELIONparticle selection
2PHENIX1.20.1_4487model refinement
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.82 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 469550 / Symmetry type: POINT
RefinementHighest resolution: 2.82 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)

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