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- PDB-9t00: Crystal structure of prethrombin-2 with a peptide corresponding t... -

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Basic information

Entry
Database: PDB / ID: 9t00
TitleCrystal structure of prethrombin-2 with a peptide corresponding to the C-terminus of the heavy chain of factor Va
Components
  • Coagulation factor V heavy chain
  • Prothrombin
KeywordsBLOOD CLOTTING / enzyme / zymogen / complex
Function / homology
Function and homology information


response to vitamin K / platelet alpha granule / Cargo concentration in the ER / COPII-coated ER to Golgi transport vesicle / COPII-mediated vesicle transport / blood circulation / negative regulation of astrocyte differentiation / : / thrombospondin receptor activity / thrombin ...response to vitamin K / platelet alpha granule / Cargo concentration in the ER / COPII-coated ER to Golgi transport vesicle / COPII-mediated vesicle transport / blood circulation / negative regulation of astrocyte differentiation / : / thrombospondin receptor activity / thrombin / thrombin-activated receptor signaling pathway / Defective factor XII causes hereditary angioedema / 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) / positive regulation of collagen biosynthetic process / negative regulation of platelet activation / negative regulation of blood coagulation / negative regulation of fibrinolysis / positive regulation of blood coagulation / negative regulation of proteolysis / 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 / regulation of cytosolic calcium ion concentration / : / negative regulation of cytokine production involved in inflammatory response / endoplasmic reticulum-Golgi intermediate compartment membrane / platelet alpha granule lumen / Regulation of Complement cascade / positive regulation of release of sequestered calcium ion into cytosol / positive regulation of receptor signaling pathway via JAK-STAT / acute-phase response / Cell surface interactions at the vascular wall / Peptide ligand-binding receptors / growth factor activity / Post-translational protein phosphorylation / response to wounding / lipopolysaccharide binding / platelet activation / 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 / Platelet degranulation / heparin binding / extracellular vesicle / Thrombin signalling through proteinase activated receptors (PARs) / Dengue Virus-Host Interactions / antimicrobial humoral immune response mediated by antimicrobial peptide / blood microparticle / extracellular matrix / G alpha (q) signalling events / cell surface receptor signaling pathway / endoplasmic reticulum lumen / receptor ligand activity / copper ion binding / serine-type endopeptidase activity / signaling receptor binding / calcium ion binding / proteolysis / : / extracellular exosome / extracellular region / membrane / plasma membrane
Similarity search - Function
Coagulation factor 5/8-like / : / Multicopper oxidases, conserved site / Multicopper oxidases signature 1. / Coagulation factors 5/8 type C domain (FA58C) signature 2. / 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. / F5/8 type C domain / Coagulation factor 5/8 C-terminal domain ...Coagulation factor 5/8-like / : / Multicopper oxidases, conserved site / Multicopper oxidases signature 1. / Coagulation factors 5/8 type C domain (FA58C) signature 2. / 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. / F5/8 type C domain / Coagulation factor 5/8 C-terminal domain / Prothrombin/thrombin / Thrombin light chain / Thrombin light chain domain superfamily / : / Thrombin light chain / Multicopper oxidase, N-terminal / Multicopper oxidase / Kringle domain / Kringle / Kringle, conserved site / Kringle superfamily / Kringle domain signature. / Kringle domain profile. / Kringle 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 / Cupredoxin / 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. / Serine proteases, trypsin family, serine active site. / Peptidase S1A, chymotrypsin family / 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 V
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.8 Å
AuthorsHuntington, J.A. / Ustok, F.I.
Funding support United Kingdom, 2items
OrganizationGrant numberCountry
British Heart FoundationRG/16/9/32391 United Kingdom
British Heart FoundationPG/24/11721 United Kingdom
CitationJournal: EMBO J / Year: 2026
Title: Prothrombinase processivity is conferred by substrate allostery.
Authors: Fatma Işık Üstok / Alexandre Faille / Alan J Warren / James A Huntington /
Abstract: The prothrombinase complex, comprised of factor (f) Xa and fVa, converts prothrombin to thrombin through sequential cleavage at two sites in a rapid and processive manner. The molecular basis of ...The prothrombinase complex, comprised of factor (f) Xa and fVa, converts prothrombin to thrombin through sequential cleavage at two sites in a rapid and processive manner. The molecular basis of prothrombin processing is an enzymatical mystery that to solve requires structural insight into how the substrate and intermediate bind to prothrombinase. Here we present two 3.1 Å cryo-EM structures of prothrombinase bound to prothrombin and to meizothrombin. The prothrombin complex revealed a surprising interaction between the end of the heavy chain of fVa with exosite I of prothrombin, accounting for 70% of the contact interface. Triggering of the zymogen-to-protease conformational change following cleavage at Arg320 alters all domain-domain and fVa interactions observed for prothrombin, and results in a large-scale rearrangement of meizothrombin that presents the second cleavage site (Arg271) for processing. Together, these structures reveal a remarkable enzymatic mechanism that requires the active participation of the substrate itself, and introduces a new paradigm of 'substrate allostery'.
History
DepositionOct 16, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 12, 2026Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Prothrombin
B: Coagulation factor V heavy chain
C: Prothrombin
D: Coagulation factor V heavy chain


Theoretical massNumber of molelcules
Total (without water)77,8984
Polymers77,8984
Non-polymers00
Water19811
1
A: Prothrombin
B: Coagulation factor V heavy chain


Theoretical massNumber of molelcules
Total (without water)38,9492
Polymers38,9492
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1220 Å2
ΔGint-4 kcal/mol
Surface area14890 Å2
MethodPISA
2
C: Prothrombin
D: Coagulation factor V heavy chain


Theoretical massNumber of molelcules
Total (without water)38,9492
Polymers38,9492
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1130 Å2
ΔGint-5 kcal/mol
Surface area14430 Å2
MethodPISA
Unit cell
Length a, b, c (Å)51.416, 51.567, 65.992
Angle α, β, γ (deg.)82.900, 85.326, 65.901
Int Tables number1
Space group name H-MP1
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails (eV)
11A
21C
32B
42D

NCS domain segments:

Beg auth comp-ID: SER / Beg label comp-ID: SER

Dom-IDComponent-IDEns-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
111PHEPHEAA275 - 57710 - 312
211PHEPHECC275 - 57710 - 312
322ILEILEBB692 - 7087 - 23
422ILEILEDD692 - 7087 - 23

NCS ensembles :
IDDetails (eV)
1Local NCS retraints between domains: 1 2
2Local NCS retraints between domains: 3 4

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Components

#1: Protein Prothrombin / Coagulation factor II


Mass: 36046.152 Da / Num. of mol.: 2 / Mutation: S525A
Source method: isolated from a genetically manipulated source
Details: Prothrombin numbering is used / Source: (gene. exp.) Homo sapiens (human) / Gene: F2 / Production host: Escherichia coli (E. coli) / References: UniProt: P00734, thrombin
#2: Protein/peptide Coagulation factor V heavy chain


Mass: 2902.776 Da / Num. of mol.: 2 / Source method: obtained synthetically / Details: Tyrosines are phosporylated / Source: (synth.) Homo sapiens (human) / References: UniProt: P12259
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 11 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestN
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.03 Å3/Da / Density % sol: 39.51 %
Crystal growTemperature: 292 K / Method: vapor diffusion, sitting drop
Details: 0.2 M NaCl (Salt) 0.1 M TRIS 8.5 pH (Buffer) 25 %w/v PEG 3350 (Precipitant)

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.7838 Å
DetectorType: DECTRIS EIGER2 XE 16M / Detector: PIXEL / Date: Oct 9, 2025
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.7838 Å / Relative weight: 1
ReflectionResolution: 2.8→38.76 Å / Num. obs: 15006 / % possible obs: 99.2 % / Redundancy: 3.7 % / CC1/2: 0.95 / Rmerge(I) obs: 0.244 / Net I/σ(I): 3
Reflection shellResolution: 2.8→2.95 Å / Redundancy: 3.4 % / Rmerge(I) obs: 1.032 / Mean I/σ(I) obs: 0.7 / Num. unique obs: 2190 / CC1/2: 0.432 / % possible all: 98.9

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Processing

Software
NameVersionClassification
REFMAC5.8.0431refinement
xia2data reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.8→38.76 Å / Cor.coef. Fo:Fc: 0.899 / Cor.coef. Fo:Fc free: 0.844 / SU B: 40.859 / SU ML: 0.681 / Cross valid method: THROUGHOUT / ESU R Free: 0.521
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflectionSelection details
Rfree0.3045 719 4.8 %RANDOM
Rwork0.2587 14261 --
all0.261 ---
obs-14980 99.074 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 47.074 Å2
Baniso -1Baniso -2Baniso -3
1--3.825 Å22.451 Å2-0.426 Å2
2---1.163 Å2-2.27 Å2
3---6.939 Å2
Refinement stepCycle: LAST / Resolution: 2.8→38.76 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5114 0 0 11 5125
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0010.0125244
X-RAY DIFFRACTIONr_bond_other_d00.0164854
X-RAY DIFFRACTIONr_angle_refined_deg0.7851.8287102
X-RAY DIFFRACTIONr_angle_other_deg0.2661.78211159
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.0015631
X-RAY DIFFRACTIONr_dihedral_angle_2_deg5.187548
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.1810878
X-RAY DIFFRACTIONr_dihedral_angle_6_deg9.47910249
X-RAY DIFFRACTIONr_chiral_restr0.050.2738
X-RAY DIFFRACTIONr_gen_planes_refined0.0020.026295
X-RAY DIFFRACTIONr_gen_planes_other00.021281
X-RAY DIFFRACTIONr_nbd_refined0.2280.21173
X-RAY DIFFRACTIONr_symmetry_nbd_other0.240.25123
X-RAY DIFFRACTIONr_nbtor_refined0.1870.22562
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0820.22637
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.2510.2155
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.0070.21
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.2550.210
X-RAY DIFFRACTIONr_nbd_other0.2620.250
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.2140.25
X-RAY DIFFRACTIONr_mcbond_it1.2954.8662542
X-RAY DIFFRACTIONr_mcbond_other1.2954.8662542
X-RAY DIFFRACTIONr_mcangle_it2.3878.7233167
X-RAY DIFFRACTIONr_mcangle_other2.3878.7243168
X-RAY DIFFRACTIONr_scbond_it0.854.8442702
X-RAY DIFFRACTIONr_scbond_other0.854.8452703
X-RAY DIFFRACTIONr_scangle_it1.648.8993935
X-RAY DIFFRACTIONr_scangle_other1.648.8993936
X-RAY DIFFRACTIONr_lrange_it4.51746.2345961
X-RAY DIFFRACTIONr_lrange_other4.51746.2355962
X-RAY DIFFRACTIONr_ncsr_local_group_10.1140.059403
X-RAY DIFFRACTIONr_ncsr_local_group_20.1380.05468
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDRefine-IDTypeRms dev position (Å)Weight position
11AX-RAY DIFFRACTIONLocal ncs0.114210.05009
12CX-RAY DIFFRACTIONLocal ncs0.114210.05009
23BX-RAY DIFFRACTIONLocal ncs0.13840.05006
24DX-RAY DIFFRACTIONLocal ncs0.13840.05006
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.8-2.8720.392500.4141083X-RAY DIFFRACTION98.3507
2.872-2.9510.434430.403996X-RAY DIFFRACTION98.8582
2.951-3.0360.367470.3811007X-RAY DIFFRACTION98.5047
3.036-3.1280.372410.36953X-RAY DIFFRACTION98.8072
3.128-3.230.424420.344944X-RAY DIFFRACTION98.5015
3.23-3.3430.335510.341896X-RAY DIFFRACTION99.2663
3.343-3.4680.408490.292886X-RAY DIFFRACTION99.1516
3.468-3.6090.34400.273823X-RAY DIFFRACTION99.1954
3.609-3.7680.317550.272791X-RAY DIFFRACTION99.2958
3.768-3.950.293360.244809X-RAY DIFFRACTION99.4118
3.95-4.1610.257360.216717X-RAY DIFFRACTION99.3404
4.161-4.410.23310.185718X-RAY DIFFRACTION99.3369
4.41-4.710.263410.183665X-RAY DIFFRACTION99.5769
4.71-5.0810.251290.168598X-RAY DIFFRACTION99.5238
5.081-5.5570.233140.188577X-RAY DIFFRACTION99.3277
5.557-6.1970.307450.245486X-RAY DIFFRACTION99.6248
6.197-7.1250.317240.235446X-RAY DIFFRACTION99.5763
7.125-8.6540.196180.21397X-RAY DIFFRACTION99.5204
8.654-11.9450.21180.17285X-RAY DIFFRACTION100
11.945-38.760.21690.295184X-RAY DIFFRACTION98.9744

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