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- PDB-9bux: Structure of GGCX-BGP-menaquinone-4 epoxide complex -

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Basic information

Entry
Database: PDB / ID: 9bux
TitleStructure of GGCX-BGP-menaquinone-4 epoxide complex
Components
  • Osteocalcin
  • Vitamin K-dependent gamma-carboxylase
KeywordsMEMBRANE PROTEIN / LYASE/SUBSTRATE / vitamin K cycle / LYASE-SUBSTRATE complex
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 / Defective gamma-carboxylation of F9 / vitamin binding / vitamin K metabolic process / positive regulation of neurotransmitter secretion / response to vitamin K / regulation of osteoclast differentiation / negative regulation of neurotransmitter secretion / cellular response to vitamin D / regulation of bone mineralization / response to vitamin D / regulation of bone resorption / bone mineralization / response to zinc ion / response to testosterone / RUNX2 regulates osteoblast differentiation / response to gravity / skeletal system development / response to mechanical stimulus / 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 / stem cell differentiation / regulation of cellular response to insulin stimulus / response to glucocorticoid / response to activity / protein modification process / brain development / protein maturation / bone development / hormone activity / cellular response to growth factor stimulus / response to estrogen / Golgi lumen / cognition / osteoblast differentiation / blood coagulation / glucose homeostasis / cellular response to insulin stimulus / vesicle / response to ethanol / perikaryon / learning or memory / cell adhesion / response to xenobiotic stimulus / endoplasmic reticulum lumen / calcium ion binding / lipid 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
: / CHOLESTEROL / Chem-POV / Osteocalcin / Vitamin K-dependent gamma-carboxylase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.06 Å
AuthorsWang, R. / Qi, X.
Funding support United States, 1items
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, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 29, 2025Provider: repository / Type: Initial release
Revision 1.1Feb 12, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.pdbx_database_id_PubMed / _citation.title ..._citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name / _em_admin.last_update
Revision 1.2Mar 26, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID / _em_admin.last_update

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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: Osteocalcin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)102,9318
Polymers100,4572
Non-polymers2,4746
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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Protein , 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: 88652.609 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 Osteocalcin / Bone Gla protein / BGP / Gamma-carboxyglutamic acid-containing protein


Mass: 11804.439 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BGLAP / Production host: Homo sapiens (human) / References: UniProt: P02818

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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.: 1
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.: 2
Source method: isolated from a genetically manipulated source
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 , 3 types, 3 molecules

#5: Chemical ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H46O
#6: Chemical ChemComp-POV / (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate / POPC


Mass: 760.076 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C42H82NO8P / Comment: phospholipid*YM
#7: Chemical ChemComp-A1AT1 / (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 / menaquinone-4 epoxide


Mass: 460.648 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C31H40O3

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Details

Has ligand of interestN
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: GGCX-BGP-menaquinone-4 epoxide complex / 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

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: NONE
3D reconstructionResolution: 3.06 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 195408 / Symmetry type: POINT

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