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- PDB-2f9b: Discovery of Novel Heterocyclic Factor VIIa Inhibitors -

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Basic information

Entry
Database: PDB / ID: 2f9b
TitleDiscovery of Novel Heterocyclic Factor VIIa Inhibitors
Components
  • (Coagulation factor VII) x 2
  • Tissue factor
KeywordsHYDROLASE/BLOOD CLOTTING / serine protease / short hydrogen bond / active site-directed inhibitor / HYDROLASE-BLOOD CLOTTING 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 / Laminin / Coagulation Factor Xa inhibitory site ...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 / Laminin / Coagulation Factor Xa inhibitory site / Laminin / 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 / 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-N1H / Coagulation factor VII / Tissue factor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.54 Å
AuthorsRai, R. / Kolesnikov, A. / Sprengeler, P.A. / Torkelson, S. / Ton, T. / Katz, B.A. / Yu, C. / Hendrix, J. / Shrader, W.D. / Stephens, R. ...Rai, R. / Kolesnikov, A. / Sprengeler, P.A. / Torkelson, S. / Ton, T. / Katz, B.A. / Yu, C. / Hendrix, J. / Shrader, W.D. / Stephens, R. / Cabuslay, R. / Sanford, E. / Young, W.B.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2006
Title: Discovery of novel heterocyclic factor VIIa inhibitors.
Authors: Rai, R. / Kolesnikov, A. / Sprengeler, P.A. / Torkelson, S. / Ton, T. / Katz, B.A. / Yu, C. / Hendrix, J. / Shrader, W.D. / Stephens, R. / Cabuslay, R. / Sanford, E. / Young, W.B.
History
DepositionDec 5, 2005Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 28, 2006Provider: repository / Type: Initial release
Revision 1.1May 1, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Oct 18, 2017Group: Refinement description / Category: software
Revision 1.4Aug 30, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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)70,2944
Polymers69,8903
Non-polymers4041
Water2,756153
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5490 Å2
ΔGint-14 kcal/mol
Surface area22100 Å2
MethodPISA
Unit cell
Length a, b, c (Å)78.070, 68.940, 78.730
Angle α, β, γ (deg.)90.00, 90.17, 90.00
Int Tables number4
Space group name H-MP1211
DetailsThe biological assembly is contained in the asymmetic unit (factor VIIa light chain, factor VIIa heavy chain, soluble tissue factor, and the inhibitor)

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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 / Cell line (production host): embryonic kidney cell line 293 / Production host: Homo sapiens (human) / References: UniProt: P08709, coagulation factor VIIa
#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 / Cell line (production host): embryonic kidney cell line 293 / Production host: Homo sapiens (human) / References: UniProt: P08709, coagulation factor VIIa
#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-N1H / {5-(5-AMINO-1H-PYRROLO[3,2-B]PYRIDIN-2-YL)-6-HYDROXY-3'-NITRO-BIPHENYL-3-YL]-ACETIC ACID


Mass: 404.376 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H16N4O5
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 153 / 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: 3.03 Å3/Da / Density % sol: 59.41 %
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 290K

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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 210 / Detector: CCD / Date: Jan 27, 2003
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.5→20 Å / Num. all: 28395 / Num. obs: 28367 / % possible obs: 99.9 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0
Reflection shellResolution: 2.54→2.65 Å / % possible all: 99.9

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Processing

Software
NameVersionClassification
DENZOdata reduction
XTALVIEWrefinement
X-PLOR3.851refinement
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1DAN

1dan


Resolution: 2.54→20 Å / σ(F): 0
RfactorNum. reflectionSelection details
Rfree0.286 2673 RANDOM
Rwork0.226 --
all0.23 26404 -
obs0.23 26404 -
Refinement stepCycle: LAST / Resolution: 2.54→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3874 0 30 155 4059
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONx_bond_d0.018
X-RAY DIFFRACTIONx_angle_deg3.98
X-RAY DIFFRACTIONx_dihedral_angle_d23.9
X-RAY DIFFRACTIONx_improper_angle_d0.47

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