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- PDB-9yq8: Cryo-EM complex of meizothrombinDESF1, factor Xa, and factor Va -

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Basic information

Entry
Database: PDB / ID: 9yq8
TitleCryo-EM complex of meizothrombinDESF1, factor Xa, and factor Va
Components
  • Coagulation factor V heavy chain
  • Coagulation factor Va light chain
  • Coagulation factor X
  • Meizothrombin
  • Thrombin heavy chain
KeywordsBLOOD CLOTTING / Coagulation cascade / Serine Proteases / Thrombotic / Clotting Factors
Function / homology
Function and homology information


response to vitamin K / coagulation factor Xa / platelet alpha granule / Cargo concentration in the ER / COPII-coated ER to Golgi transport vesicle / Defective factor IX causes thrombophilia / Defective cofactor function of FVIIIa variant / Defective F9 variant does not activate FX / COPII-mediated vesicle transport / : ...response to vitamin K / coagulation factor Xa / platelet alpha granule / Cargo concentration in the ER / COPII-coated ER to Golgi transport vesicle / Defective factor IX causes thrombophilia / Defective cofactor function of FVIIIa variant / Defective F9 variant does not activate FX / COPII-mediated vesicle transport / : / : / blood circulation / thrombospondin receptor activity / thrombin / thrombin-activated receptor signaling pathway / Defective factor XII causes hereditary angioedema / negative regulation of astrocyte differentiation / regulation of blood coagulation / neutrophil-mediated killing of gram-negative bacterium / positive regulation of phospholipase C-activating G protein-coupled receptor signaling pathway / Defective F8 cleavage by thrombin / Platelet Aggregation (Plug Formation) / ligand-gated ion channel signaling pathway / positive regulation of collagen biosynthetic process / negative regulation of platelet activation / negative regulation of blood coagulation / negative regulation of fibrinolysis / blood coagulation, fibrin clot formation / positive regulation of blood coagulation / positive regulation of TOR signaling / 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 / regulation of cytosolic calcium ion concentration / fibrinolysis / : / negative regulation of proteolysis / endoplasmic reticulum-Golgi intermediate compartment membrane / negative regulation of cytokine production involved in inflammatory response / platelet alpha granule lumen / Regulation of Complement cascade / Peptide ligand-binding receptors / positive regulation of release of sequestered calcium ion into cytosol / acute-phase response / Cell surface interactions at the vascular wall / positive regulation of receptor signaling pathway via JAK-STAT / growth factor activity / Post-translational protein phosphorylation / lipopolysaccharide binding / platelet activation / phospholipid binding / response to wounding / positive regulation of protein localization to nucleus / Golgi lumen / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / positive regulation of reactive oxygen species metabolic process / blood coagulation / positive regulation of insulin secretion / Platelet degranulation / antimicrobial humoral immune response mediated by antimicrobial peptide / regulation of cell shape / heparin binding / extracellular vesicle / Thrombin signalling through proteinase activated receptors (PARs) / positive regulation of cell growth / blood microparticle / G alpha (q) signalling events / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / cell surface receptor signaling pathway / positive regulation of cell migration / endoplasmic reticulum lumen / receptor ligand activity / copper ion binding / serine-type endopeptidase activity / signaling receptor binding / external side of plasma membrane / calcium ion binding / positive regulation of cell population proliferation / proteolysis / : / extracellular exosome / extracellular region / membrane / plasma membrane
Similarity search - Function
Coagulation factor 5/8-like / : / Coagulation factors 5/8 type C domain (FA58C) signature 2. / Multicopper oxidases, conserved site / Multicopper oxidases signature 1. / Coagulation factors 5/8 type C domain (FA58C) signature 1. / Coagulation factor 5/8 C-terminal domain, discoidin domain / Coagulation factors 5/8 type C domain (FA58C) profile. / Peptidase S1A, coagulation factor VII/IX/X/C/Z / F5/8 type C domain ...Coagulation factor 5/8-like / : / Coagulation factors 5/8 type C domain (FA58C) signature 2. / Multicopper oxidases, conserved site / Multicopper oxidases signature 1. / Coagulation factors 5/8 type C domain (FA58C) signature 1. / Coagulation factor 5/8 C-terminal domain, discoidin domain / Coagulation factors 5/8 type C domain (FA58C) profile. / Peptidase S1A, coagulation factor VII/IX/X/C/Z / F5/8 type C domain / : / Coagulation factor 5/8 C-terminal domain / Coagulation factor-like, Gla domain superfamily / Prothrombin/thrombin / Thrombin light chain / Thrombin light chain domain superfamily / : / Thrombin light chain / Multicopper oxidase, N-terminal / Multicopper oxidase / Coagulation Factor Xa inhibitory site / EGF-like domain / EGF-type aspartate/asparagine hydroxylation site / EGF-like calcium-binding, conserved site / Calcium-binding EGF-like domain signature. / Kringle domain / Kringle / Kringle, conserved site / Kringle superfamily / Kringle domain signature. / Kringle domain profile. / Kringle domain / 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. / Kringle-like fold / Epidermal growth factor-like domain. / EGF-like domain profile. / EGF-like domain signature 1. / EGF-like domain signature 2. / Cupredoxin / EGF-like domain / Galactose-binding-like domain superfamily / Serine proteases, trypsin family, histidine active site / Serine proteases, trypsin family, serine active site / Serine proteases, trypsin family, histidine active site. / Peptidase S1A, chymotrypsin family / Serine proteases, trypsin family, serine active site. / Serine proteases, trypsin domain profile. / Trypsin-like serine protease / Serine proteases, trypsin domain / Trypsin / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan
Similarity search - Domain/homology
Prothrombin / Coagulation factor X / Coagulation factor V
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.84 Å
AuthorsStojanovski, B.M. / Mohammed, B.M. / Basore, K. / Di Cera, E.
Funding support United States, 5items
OrganizationGrant numberCountry
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)HL049413 United States
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)HL139554 United States
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)HL147821 United States
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)P30DK020579 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)P30CA091842 United States
CitationJournal: Blood / Year: 2026
Title: Molecular mechanism of cleavage at R271 during prothrombin activation revealed by cryo-EM.
Authors: Bosko Stojanovski / Bassem M Mohammed / Katherine Basore / Enrico Di Cera /
Abstract: The conversion of the inactive zymogen prothrombin to the active protease thrombin in the common pathway of the coagulation cascade is the molecular event responsible for the pathophysiology of ...The conversion of the inactive zymogen prothrombin to the active protease thrombin in the common pathway of the coagulation cascade is the molecular event responsible for the pathophysiology of hemostasis and thrombosis. The conversion entails two proteolytic cleavages at R320 and R271 by the prothrombinase complex composed of the enzyme factor Xa (fXa), the cofactor fVa, Ca2+ and phospholipids. A recent cryogenic electron microscopy (cryo-EM) structure revealed how cleavage at R320 generates the active intermediate meizothrombin in the first step of the activation pathway. Here we present the 3.8 Å resolution cryo-EM structure of a truncated form of meizothrombin (mzTDF1) bound to fVa and fXa that reveals how the second cleavage at R271 generates thrombin. The cleavage is brokered by molecular contacts that involve mostly the protease domains of mzTDF1 and fXa and largely validate the results from biochemical studies. The switch in cleavage site from R320 to R271 involves a significant reorientation rather than conformational transitions of the protease domain of mzTDF1 that moves the guanidinium group of R271 more than 20 Å into the primary specificity pocket of fXa. The findings complete the cryo-EM structural analysis of prothrombin activation along the meizothrombin pathway and advance our molecular understanding of a reaction critical to the pathophysiology of blood coagulation.
History
DepositionOct 15, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 20, 2026Provider: repository / Type: Initial release
Revision 1.0May 20, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0May 20, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0May 20, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
E: Coagulation factor X
A: Coagulation factor Va light chain
L: Meizothrombin
H: Thrombin heavy chain
B: Coagulation factor V heavy chain


Theoretical massNumber of molelcules
Total (without water)237,1605
Polymers237,1605
Non-polymers00
Water00
1


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

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Components

#1: Protein Coagulation factor X / Stuart factor / Stuart-Prower factor


Mass: 38589.340 Da / Num. of mol.: 1 / Mutation: S379A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: F10 / Production host: Mesocricetus auratus (golden hamster) / References: UniProt: P00742, coagulation factor Xa
#2: Protein Coagulation factor Va light chain / Activated protein C cofactor / Proaccelerin / labile factor


Mass: 75283.008 Da / Num. of mol.: 1 / Fragment: Domains C1, C2, and A3 (UNP residues 1574-2224) / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P12259
#3: Protein Meizothrombin / Coagulation factor II


Mass: 16503.898 Da / Num. of mol.: 1 / Fragment: kringle 2/A-chain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: F2 / Cell (production host): Baby hamster kidney / Production host: Mesocricetus auratus (golden hamster) / References: UniProt: P00734, thrombin
#4: Protein Thrombin heavy chain / Coagulation factor II


Mass: 29578.055 Da / Num. of mol.: 1 / Mutation: S525A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: F2 / Production host: Mesocricetus auratus (golden hamster) / References: UniProt: P00734, thrombin
#5: Protein Coagulation factor V heavy chain / Activated protein C cofactor / Proaccelerin / labile factor


Mass: 77205.906 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P12259
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

Component
IDNameTypeEntity IDParent-IDSource
1Complex of meizothrombinDESF1, factor Xa and factor VaCOMPLEXall0MULTIPLE SOURCES
2Coagulation factor X domains and Thrombin chainsCOMPLEX#1, #3-#41RECOMBINANT
3Coagulation factor V light and heavy chainsCOMPLEX#2, #51NATURAL
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
22Homo sapiens (human)9606
33Homo sapiens (human)9606
Source (recombinant)Organism: Mesocricetus auratus (golden hamster)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS / Details: Preliminary grid screening was performed manually.
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 75000 X / Nominal defocus max: 2400 nm / Nominal defocus min: 1000 nm / Cs: 0.01 mm / C2 aperture diameter: 150 µm / Alignment procedure: ZEMLIN TABLEAU
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 51 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k) / Num. of grids imaged: 3 / Num. of real images: 5179 / Details: 28% of images collected at 30 degree stage tilt.
EM imaging opticsSpherical aberration corrector: Microscope is outfitted with a Cs image corrector with two hexapole elements.
Image scansWidth: 4096 / Height: 4096

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Processing

EM software
IDNameCategoryFitting-ID
1cryoSPARCparticle selection
2EPUimage acquisition
4cryoSPARCCTF correction
7UCSF ChimeraXmodel fitting1
9PHENIXmodel refinement1
10Cootmodel refinement1
12UCSF ChimeraXmodel fitting2
13PHENIXmodel refinement2
14Cootmodel refinement2
15UCSF ChimeraXmodel fitting3
16PHENIXmodel refinement3
17Cootmodel refinement3
21cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.84 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 38200 / Symmetry type: POINT
Atomic model building
IDProtocolSpace
1RIGID BODY FITREAL
2RIGID BODY FITREAL
3RIGID BODY FITREAL
Atomic model building
IDPDB-ID 3D fitting-IDAccession codeInitial refinement model-IDSource nameType
13e6p

3e6p

13e6p1PDBexperimental model
21xkb

1xkb

21xkb2PDBexperimental model
38tn9

8tn9

38tn93PDBexperimental model

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