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- PDB-2flb: Discovery of a Novel Hydroxy Pyrazole Based Factor IXa Inhibitor -

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Basic information

Entry
Database: PDB / ID: 2flb
TitleDiscovery of a Novel Hydroxy Pyrazole Based Factor IXa Inhibitor
Components
  • (Coagulation factor VII) x 2
  • Tissue factor
KeywordsHYDROLASE/BLOOD CLOTTING / active site-directed / short hydrogen bond-mediated / pyrazole-based inhibitor / HYDROLASE-BLOOD CLOTTING COMPLEX
Function / homology
Function and homology information


activation of plasma proteins involved in acute inflammatory response / activation of blood coagulation via clotting cascade / 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 plasma proteins involved in acute inflammatory response / activation of blood coagulation via clotting cascade / 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 / phospholipid binding / protein processing / 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 / external side of plasma membrane / endoplasmic reticulum lumen / signaling receptor binding / serine-type endopeptidase activity / 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 / Laminin ...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 / Laminin / Laminin / EGF-type aspartate/asparagine hydroxylation site / EGF-like domain / 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 / Ribbon / 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-6NH / Coagulation factor VII / Tissue factor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.95 Å
AuthorsKatz, B.A.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2006
Title: Discovery of novel hydroxy pyrazole based factor IXa inhibitor.
Authors: Vijaykumar, D. / Sprengeler, P.A. / Shaghafi, M. / Spencer, J.R. / Katz, B.A. / Yu, C. / Rai, R. / Young, W.B. / Schultz, B. / Janc, J.
History
DepositionJan 5, 2006Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 4, 2006Provider: repository / Type: Initial release
Revision 1.1May 1, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Oct 11, 2017Group: Data collection / Refinement description / Category: reflns / software / Item: _reflns.percent_possible_obs

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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)70,2084
Polymers69,8903
Non-polymers3181
Water5,783321
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5510 Å2
ΔGint-10 kcal/mol
Surface area22500 Å2
MethodPISA
Unit cell
Length a, b, c (Å)78.450, 69.030, 78.760
Angle α, β, γ (deg.)90.00, 90.21, 90.00
Int Tables number4
Space group name H-MP1211
DetailsThe assembly is one molecule of factor VIIa (light chain plus heavy chain), one molecule of tissue factor, and one inhibitor molecule (2-(4-Hydroxy-5-phenyl-1H-pyrazol-3-yl)-1H-benzoimidazole-5-carboxamidine

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Components

#1: Protein Coagulation factor VII /


Mass: 17046.975 Da / Num. of mol.: 1 / Fragment: light chain, residues 61-212
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: F7 / Production host: Escherichia coli (E. coli) / References: UniProt: P08709
#2: Protein Coagulation factor VII /


Mass: 28103.256 Da / Num. of mol.: 1 / Fragment: heavy chain, residues 213-466
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: F7 / Production host: Escherichia coli (E. coli) / References: UniProt: P08709
#3: Protein Tissue factor / / TF / Coagulation factor III / Thromboplastin / CD142 antigen


Mass: 24739.434 Da / Num. of mol.: 1 / Fragment: residues 34-251
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: F3 / Plasmid: PET-21A(+) / Production host: Escherichia coli (E. coli) / Strain (production host): BL21-DES3 / References: UniProt: P13726
#4: Chemical ChemComp-6NH / 2-(4-HYDROXY-5-PHENYL-1H-PYRAZOL-3-YL)-1H-BENZOIMIDAZOLE-5-CARBOXAMIDINE


Mass: 318.333 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H14N6O
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 321 / 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: 3.05 Å3/Da / Density % sol: 59.67 %
Crystal growTemperature: 290 K / Method: vapor diffusion, hanging drop / pH: 7.2
Details: 0.1 M CITRATE, 16-18% PEG5000 MME, pH 7.2, VAPOR DIFFUSION, HANGING DROP, temperature 290.0K

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Data collection

DiffractionMean temperature: 113 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Jun 21, 2004
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.95→20 Å / Num. all: 57297 / Num. obs: 57297 / Observed criterion σ(F): 0 / Observed criterion σ(I): 0
Reflection shellResolution: 1.95→2.04 Å / % possible all: 81.34

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Processing

Software
NameVersionClassification
SCALEPACKdata scaling
X-PLORmodel building
X-PLOR3.851refinement
X-PLORphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.95→7 Å / σ(F): 2
RfactorNum. reflectionSelection details
Rfree0.28 5085 RANDOM
Rwork0.247 --
all0.261 56089 -
obs0.25 50969 -
Refinement stepCycle: LAST / Resolution: 1.95→7 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3933 0 24 321 4278
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONx_bond_d0.016
X-RAY DIFFRACTIONx_angle_deg3.27
X-RAY DIFFRACTIONx_dihedral_angle_d26.1
X-RAY DIFFRACTIONx_improper_angle_d1.3

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