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- PDB-1z6j: Crystal Structure of a ternary complex of Factor VIIa/Tissue Fact... -

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Basic information

Entry
Database: PDB / ID: 1z6j
TitleCrystal Structure of a ternary complex of Factor VIIa/Tissue Factor/Pyrazinone Inhibitor
Components
  • (Coagulation factor ...) x 2
  • Tissue factor
KeywordsHYDROLASE / Blood coagulation / serine protease / thrombosis / gla / pyrazinone / benzamidine / tissue factor / cofactor / enzyme inhibitor complex
Function / homology
Function and homology information


activation of blood coagulation via clotting cascade / activation of plasma proteins involved in acute inflammatory response / coagulation factor VIIa / response to Thyroid stimulating hormone / response to 2,3,7,8-tetrachlorodibenzodioxine / response to astaxanthin / response to thyrotropin-releasing hormone / response to genistein / serine-type peptidase complex / positive regulation of platelet-derived growth factor receptor signaling pathway ...activation of blood coagulation via clotting cascade / activation of plasma proteins involved in acute inflammatory response / coagulation factor VIIa / response to Thyroid stimulating hormone / response to 2,3,7,8-tetrachlorodibenzodioxine / response to astaxanthin / response to thyrotropin-releasing hormone / response to genistein / serine-type peptidase complex / positive regulation of platelet-derived growth factor receptor signaling pathway / response to vitamin K / response to carbon dioxide / response to thyroxine / NGF-stimulated transcription / response to cholesterol / response to growth hormone / positive regulation of positive chemotaxis / Extrinsic Pathway of Fibrin Clot Formation / positive regulation of leukocyte chemotaxis / cytokine receptor activity / positive regulation of TOR signaling / positive regulation of blood coagulation / animal organ regeneration / Gamma-carboxylation of protein precursors / Transport of gamma-carboxylated protein precursors from the endoplasmic reticulum to the Golgi apparatus / Removal of aminoterminal propeptides from gamma-carboxylated proteins / positive regulation of endothelial cell proliferation / serine-type peptidase activity / BMAL1:CLOCK,NPAS2 activates circadian gene expression / positive regulation of interleukin-8 production / protein processing / phospholipid binding / cytokine-mediated signaling pathway / Golgi lumen / circadian rhythm / response to estrogen / positive regulation of angiogenesis / activation of cysteine-type endopeptidase activity involved in apoptotic process / blood coagulation / response to estradiol / collagen-containing extracellular matrix / protease binding / vesicle / response to hypoxia / positive regulation of cell migration / endoplasmic reticulum lumen / external side of plasma membrane / serine-type endopeptidase activity / signaling receptor binding / calcium ion binding / positive regulation of gene expression / cell surface / extracellular space / extracellular region / membrane / plasma membrane
Similarity search - Function
Tissue factor / Tissue factor, conserved site / Tissue factor signature. / Interferon/interleukin receptor domain / Interferon-alpha/beta receptor, fibronectin type III / Tissue factor / Peptidase S1A, coagulation factor VII/IX/X/C/Z / Coagulation factor-like, Gla domain superfamily / Coagulation Factor Xa inhibitory site / EGF-like domain ...Tissue factor / Tissue factor, conserved site / Tissue factor signature. / Interferon/interleukin receptor domain / Interferon-alpha/beta receptor, fibronectin type III / Tissue factor / Peptidase S1A, coagulation factor VII/IX/X/C/Z / Coagulation factor-like, Gla domain superfamily / 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. / 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. / EGF-like domain signature 2. / EGF-like domain signature 1. / EGF-like domain / Fibronectin type III / Fibronectin type III superfamily / Serine proteases, trypsin family, histidine active site / Serine proteases, trypsin family, serine active site / Peptidase S1A, chymotrypsin family / Serine proteases, trypsin family, histidine active site. / Serine proteases, trypsin domain profile. / Serine proteases, trypsin family, serine active site. / Trypsin-like serine protease / Serine proteases, trypsin domain / Trypsin / Trypsin-like serine proteases / Thrombin, subunit H / Immunoglobulins / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan / Immunoglobulin-like fold / Immunoglobulin-like / Beta Barrel / Sandwich / Mainly Beta
Similarity search - Domain/homology
Chem-PY3 / Coagulation factor VII / Tissue factor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2 Å
AuthorsSchweitzer, B.A. / Neumann, W.L. / Rahman, H.K. / Kusturin, C.L. / Sample, K.R. / Poda, G.I. / Kurumbail, R.G. / Stevens, A.M. / Stegeman, R.A. / Stallings, W.C.
Citation
Journal: Bioorg.Med.Chem.Lett. / Year: 2005
Title: Structure-based design and synthesis of pyrazinones containing novel P1 'side pocket' moieties as inhibitors of TF/VIIa.
Authors: Schweitzer, B.A. / Neumann, W.L. / Rahman, H.K. / Kusturin, C.L. / Sample, K.R. / Poda, G.I. / Kurumbail, R.G. / Stevens, A.M. / Stegeman, R.A. / Stallings, W.C. / South, M.S.
#1: Journal: Bioorg.Med.Chem.Lett. / Year: 2003
Title: Structure-based design of pyrazinone antithrombotics as selective inhibitors of the tissue factor VIIa complex
Authors: South, M.S. / Case, B.L. / Wood, R.S. / Jones, D.E. / Hayes, M.J. / Girard, T.J. / LaChance, R.M. / Nicholson, N.S. / Clare, M. / Stevens, A.M. / Stegeman, R.A. / Stallings, W.C. / Kurumbail, R.G. / Parlow, J.J.
#2: Journal: J.Med.Chem. / Year: 2003
Title: Polymer-assisted solution-phase library synthesis and crystal structure of alpha-ketothiazoles as tissue factor VIIa inhibitors
Authors: Parlow, J.J. / Dice, T.A. / LaChance, R.M. / Girard, T.J. / Stevens, A.M. / Stegeman, R.A. / Stallings, W.C. / Kurumbail, R.G. / South, M.S.
History
DepositionMar 22, 2005Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 3, 2005Provider: repository / Type: Initial release
Revision 1.1Apr 30, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Oct 11, 2017Group: Refinement description / Category: software
Item: _software.classification / _software.contact_author ..._software.classification / _software.contact_author / _software.contact_author_email / _software.date / _software.language / _software.location / _software.name / _software.type / _software.version
Revision 1.4Jul 24, 2019Group: Data collection / Derived calculations / Refinement description
Category: software / struct_conn
Item: _software.classification / _software.contact_author ..._software.classification / _software.contact_author / _software.contact_author_email / _software.location / _software.name / _software.type / _software.version / _struct_conn.pdbx_leaving_atom_flag

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
L: Coagulation factor VII
H: Coagulation factor VII
T: Tissue factor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)69,0417
Polymers68,2833
Non-polymers7574
Water7,008389
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7150 Å2
ΔGint-43 kcal/mol
Surface area27660 Å2
MethodPISA
Unit cell
Length a, b, c (Å)69.652, 81.137, 125.577
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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Coagulation factor ... , 2 types, 2 molecules LH

#1: Protein Coagulation factor VII / Serum prothrombin conversion accelerator / SPCA / Proconvertin / Eptacog alfa


Mass: 16359.772 Da / Num. of mol.: 1 / Fragment: Light Chain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: F7 / Organ (production host): Kidney / Production host: Cricetinae (hamsters) / References: UniProt: P08709, coagulation factor VIIa
#2: Protein Coagulation factor VII / Serum prothrombin conversion accelerator / SPCA / Proconvertin / Eptacog alfa


Mass: 28103.256 Da / Num. of mol.: 1 / Fragment: Heavy Chain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: F7 / Organ (production host): kidney / Production host: Cricetinae (hamsters) / References: UniProt: P08709, coagulation factor VIIa

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Protein , 1 types, 1 molecules T

#3: Protein Tissue factor / TF / Coagulation factor III / Thromboplastin / CD142 antigen


Mass: 23820.443 Da / Num. of mol.: 1 / Fragment: Residues 33-243
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: F3 / Production host: Escherichia coli (E. coli) / References: UniProt: P13726

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Non-polymers , 4 types, 393 molecules

#4: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Ca
#5: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#6: Chemical ChemComp-PY3 / 5-[AMINO(IMINO)METHYL]-2-[({[6-[3-AMINO-5-({[(1R)-1-METHYLPROPYL]AMINO}CARBONYL)PHENYL]-3-(ISOPROPYLAMINO)-2-OXOPYRAZIN-1(2H)-YL]ACETYL}AMINO)METHYL]-N-PYRIDIN-4-YLBENZAMIDE


Mass: 652.746 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C34H40N10O4
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 389 / Source method: isolated from a natural source / Formula: H2O

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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: 2.2 Å3/Da / Density % sol: 44 %
Crystal growTemperature: 298 K / Method: vapor diffusion / pH: 7.5
Details: 50 mM citrate, 16-24% PEG 4K, 150 mM MgCl2, pH 7.5, VAPOR DIFFUSION, temperature 298K

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Data collection

DiffractionMean temperature: 110 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: MARRESEARCH / Detector: CCD / Date: Oct 23, 2002
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2→20 Å / Num. all: 47697 / Num. obs: 46245 / % possible obs: 97.2 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 3.7 % / Biso Wilson estimate: 13.5 Å2 / Rmerge(I) obs: 0.096 / Rsym value: 0.096 / Χ2: 0.992 / Net I/σ(I): 8.2
Reflection shellResolution: 2→2.07 Å / % possible obs: 94.3 % / Redundancy: 2.8 % / Rmerge(I) obs: 0.38 / Mean I/σ(I) obs: 2.3 / Num. measured obs: 4563 / Num. unique all: 4563 / Rsym value: 0.38 / Χ2: 0.823 / % possible all: 94.3

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Processing

Software
NameVersionClassificationNB
X-PLOR98.1refinement
SCALEPACKdata scaling
CNSrefinement
PDB_EXTRACT1.6data extraction
HKL-2000data reduction
X-PLORphasing
DENZOdata reduction
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2→20 Å / Isotropic thermal model: isotropic, restrained / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 0 / Stereochemistry target values: Engh & Huber / Details: Bulksolvent correction applied
RfactorNum. reflection% reflectionSelection details
Rfree0.258 4402 -random (10%)
Rwork0.2091 ---
all0.22 44217 --
obs0.22 44217 90.1 %-
Displacement parametersBiso mean: 25.848 Å2
Refinement stepCycle: LAST / Resolution: 2→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4767 0 51 389 5207
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONx_bond_d0.009
X-RAY DIFFRACTIONx_angle_deg1.67
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkRefine-IDNum. reflection obs
2-2.090.29694800.2462X-RAY DIFFRACTION4926
2.09-2.20.26545090.2297X-RAY DIFFRACTION5190
2.52-2.770.27745380.218X-RAY DIFFRACTION5608
2.77-3.170.26875860.2085X-RAY DIFFRACTION5744
3.17-3.990.24546200.1936X-RAY DIFFRACTION5896
3.99-200.22676140.1884X-RAY DIFFRACTION6016

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