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- PDB-2b7d: Factor VIIa Inhibitors: Chemical Optimization, Preclinical Pharma... -

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Basic information

Entry
Database: PDB / ID: 2b7d
TitleFactor VIIa Inhibitors: Chemical Optimization, Preclinical Pharmacokinetics, Pharmacodynamics, and Efficacy in a Baboon Thrombosis Model
Components
  • (Coagulation factor VII) x 2
  • Tissue factor
KeywordsBLOOD CLOTTING / short hydrogen bond
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-C1B / Coagulation factor VII / Tissue factor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.24 Å
AuthorsYoung, W.B. / Mordenti, J. / Torkelson, S. / Shrader, W.D. / Kolesnikov, A. / Rai, R. / Liu, L. / Hu, H. / Leahy, E.M. / Green, M.J. ...Young, W.B. / Mordenti, J. / Torkelson, S. / Shrader, W.D. / Kolesnikov, A. / Rai, R. / Liu, L. / Hu, H. / Leahy, E.M. / Green, M.J. / Sprengeler, P.A. / Katz, B.A. / Yu, C. / Janc, J.W. / Elrod, K.C. / Marzec, U.M. / Hanson, S.R.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2006
Title: Factor VIIa inhibitors: Chemical optimization, preclinical pharmacokinetics, pharmacodynamics, and efficacy in an arterial baboon thrombosis model.
Authors: Young, W.B. / Mordenti, J. / Torkelson, S. / Shrader, W.D. / Kolesnikov, A. / Rai, R. / Liu, L. / Hu, H. / Leahy, E.M. / Green, M.J. / Sprengeler, P.A. / Katz, B.A. / Yu, C. / Janc, J.W. / ...Authors: Young, W.B. / Mordenti, J. / Torkelson, S. / Shrader, W.D. / Kolesnikov, A. / Rai, R. / Liu, L. / Hu, H. / Leahy, E.M. / Green, M.J. / Sprengeler, P.A. / Katz, B.A. / Yu, C. / Janc, J.W. / Elrod, K.C. / Marzec, U.M. / Hanson, S.R.
History
DepositionOct 4, 2005Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 14, 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: Refinement description / Category: software
Revision 1.4Aug 23, 2023Group: Advisory / Data collection ...Advisory / Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_remark / 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 / _pdbx_database_remark.text / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Remark 600HETEROGEN NOTE THAT IN THE CRYSTAL A REACEMIC MIXTURE OF THE LIGAND C1B WAS USED. THE PHENOLATE ...HETEROGEN NOTE THAT IN THE CRYSTAL A REACEMIC MIXTURE OF THE LIGAND C1B WAS USED. THE PHENOLATE OXYGEN MAKES SHORT HYDROGEN BONDS WITH THE HYDROXYL GROUP OF SER195 AND A WATER.

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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)70,4224
Polymers69,8903
Non-polymers5331
Water5,513306
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5670 Å2
ΔGint-16 kcal/mol
Surface area22020 Å2
MethodPISA
Unit cell
Length a, b, c (Å)78.70, 69.03, 78.19
Angle α, β, γ (deg.)90.0, 89.49, 90.0
Int Tables number4
Space group name H-MP1211

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Components

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


Mass: 17046.975 Da / Num. of mol.: 1 / Fragment: light chain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: F7 / Cell line (production host): HEK 293 / Production host: Homo sapiens (human) / References: UniProt: P08709
#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 / Cell line (production host): HEK 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
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
#4: Chemical ChemComp-C1B / (2R)-2-[5-(5-CARBAMIMIDOYL-1H-BENZOIMIDAZOL-2-YL)-6,2'-DIHYDROXY-5'-UREIDOMETHYL-BIPHENYL-3-YL]-SUCCINIC ACID


Mass: 532.505 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H24N6O7
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 306 / 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: 3.04 Å3/Da / Density % sol: 59.51 %
Crystal growTemperature: 290 K / Method: vapor diffusion, hanging drop / pH: 7.2
Details: 0.1 M citrate, 16-18 % PEG 5K MME, pH 7.2, VAPOR DIFFUSION, HANGING DROP, temperature 290.0K

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Data collection

DiffractionMean temperature: 110 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.1 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 4 / Detector: CCD / Date: Dec 14, 2002
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.15→50 Å / Num. all: 46733 / Num. obs: 46266 / % possible obs: 99 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Rmerge(I) obs: 0.11 / Net I/σ(I): 11.3
Reflection shellResolution: 2.15→2.19 Å / % possible all: 97.1

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Processing

Software
NameVersionClassification
DENZOdata reduction
SCALEPACKdata scaling
X-sightmodel building
Accelrysmodel building
X-PLOR3.851refinement
X-SIGHTphasing
ACCELRYSphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1DAN

1dan


Resolution: 2.24→7 Å / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.289 3892 10 %RANDOM
Rwork0.247 ---
all0.25 38857 --
obs0.25 38857 --
Refinement stepCycle: LAST / Resolution: 2.24→7 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3888 0 39 306 4233
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONx_bond_d0.019
X-RAY DIFFRACTIONx_angle_deg3.98
X-RAY DIFFRACTIONx_dihedral_angle_d24.7

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