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- PDB-4isi: Structure of FACTOR VIIA in complex with the inhibitor (6S)-N-(4-... -

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Basic information

Entry
Database: PDB / ID: 4isi
TitleStructure of FACTOR VIIA in complex with the inhibitor (6S)-N-(4-CARBAMIMIDOYLBENZYL)-1-CHLORO-3-(CYCLOBUTYLAMINO)-8,8-DIETHYL-4-OXO-4,6,7,8-TETRAHYDROPYRROLO[1,2-A]PYRAZINE-6-CARBOXAMIDE
Components
  • Factor VII heavy chain
  • Factor VII light chain
KeywordsHYDROLASE/Hydrolase Inhibitor / GLYCOPROTEIN / HYDROLASE / SERINE PROTEASE / PLASMA / BLOOD COAGULATION FACTOR / PROTEIN INHIBITOR COMPLEX / CALCIUM-BINDING / HYDROLASE-Hydrolase Inhibitor complex
Function / homology
Function and homology information


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 ...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 / response to cholesterol / response to growth hormone / positive regulation of positive chemotaxis / Extrinsic Pathway of Fibrin Clot Formation / positive regulation of leukocyte chemotaxis / 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 / serine-type peptidase activity / BMAL1:CLOCK,NPAS2 activates circadian gene expression / protein processing / Golgi lumen / circadian rhythm / response to estrogen / blood coagulation / response to estradiol / collagen-containing extracellular matrix / vesicle / response to hypoxia / positive regulation of cell migration / endoplasmic reticulum lumen / serine-type endopeptidase activity / signaling receptor binding / calcium ion binding / extracellular space / extracellular region / plasma membrane
Similarity search - Function
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. ...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 / 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 / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan / Beta Barrel / Mainly Beta
Similarity search - Domain/homology
Chem-1GG / Coagulation factor VII
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Molecular Substitution / Resolution: 1.94 Å
AuthorsWei, A.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2013
Title: Design and synthesis of bicyclic pyrazinone and pyrimidinone amides as potent TF-FVIIa inhibitors.
Authors: Zhang, X. / Glunz, P.W. / Jiang, W. / Schmitt, A. / Newman, M. / Barbera, F.A. / Bozarth, J.M. / Rendina, A.R. / Wei, A. / Wen, X. / Rossi, K.A. / Luettgen, J.M. / Wong, P.C. / Knabb, R.M. / ...Authors: Zhang, X. / Glunz, P.W. / Jiang, W. / Schmitt, A. / Newman, M. / Barbera, F.A. / Bozarth, J.M. / Rendina, A.R. / Wei, A. / Wen, X. / Rossi, K.A. / Luettgen, J.M. / Wong, P.C. / Knabb, R.M. / Wexler, R.R. / Scott Priestley, E.
History
DepositionJan 16, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 27, 2013Provider: repository / Type: Initial release
Revision 1.1Mar 6, 2013Group: Database references

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
H: Factor VII heavy chain
L: Factor VII light chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,6454
Polymers34,1342
Non-polymers5112
Water3,963220
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2070 Å2
ΔGint-19 kcal/mol
Surface area13940 Å2
MethodPISA
Unit cell
Length a, b, c (Å)95.420, 95.420, 117.100
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number92
Space group name H-MP41212
Components on special symmetry positions
IDModelComponents
11H-401-

HOH

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Components

#1: Protein Factor VII heavy chain


Mass: 28103.256 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: F7 / Production host: Cricetinae (hamsters) / References: UniProt: P08709, coagulation factor VIIa
#2: Protein Factor VII light chain


Mass: 6030.827 Da / Num. of mol.: 1 / Fragment: UNP residues 150-204
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: F7 / Production host: Cricetinae (hamsters) / References: UniProt: P08709, coagulation factor VIIa
#3: Chemical ChemComp-1GG / (6S)-N-(4-carbamimidoylbenzyl)-1-chloro-3-(cyclobutylamino)-8,8-diethyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrazine-6-carboxamide


Mass: 470.995 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H31ClN6O2
#4: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Ca
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 220 / 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: 3.9 Å3/Da / Density % sol: 68.5 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6
Details: 100 mM MES, pH 6.0, 20 mM CACL2, 17.5%(W/V) PEG 6000, vapor diffusion, hanging drop, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-BM / Wavelength: 1 / Wavelength: 1 Å
DetectorType: MAR CCD 165 mm / Detector: CCD / Date: Apr 26, 2002
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.94→50 Å / Num. obs: 40495 / % possible obs: 99.9 % / Observed criterion σ(I): 0 / Redundancy: 14.1 % / Biso Wilson estimate: 15.8 Å2 / Rmerge(I) obs: 0.099 / Net I/σ(I): 60.6
Reflection shellResolution: 1.94→2.01 Å / Redundancy: 11.1 % / Rmerge(I) obs: 0.301 / Mean I/σ(I) obs: 10.9 / % possible all: 100

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Processing

Software
NameVersionClassificationNB
CNSrefinement
PDB_EXTRACT3.11data extraction
HKL-2000data reduction
HKL-2000data scaling
CNX2005refinement
RefinementMethod to determine structure: Molecular Substitution / Resolution: 1.94→32.42 Å / Rfactor Rfree error: 0.005 / Occupancy max: 1 / Occupancy min: 0.5 / Data cutoff high absF: 272346 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.229 1950 5 %RANDOM
Rwork0.209 ---
obs0.21 38783 95.7 %-
all-40422 --
Solvent computationSolvent model: FLAT MODEL / Bsol: 40.0001 Å2 / ksol: 0.3655 e/Å3
Displacement parametersBiso max: 69.01 Å2 / Biso mean: 27.2048 Å2 / Biso min: 6.6 Å2
Baniso -1Baniso -2Baniso -3
1--1.52 Å20 Å20 Å2
2---1.52 Å20 Å2
3---3.04 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.26 Å0.23 Å
Luzzati d res low-5 Å
Luzzati sigma a0.11 Å0.09 Å
Refinement stepCycle: LAST / Resolution: 1.94→32.42 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2390 0 34 220 2644
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.005
X-RAY DIFFRACTIONc_angle_deg1.1
X-RAY DIFFRACTIONc_dihedral_angle_d21.2
X-RAY DIFFRACTIONc_improper_angle_d0.99
X-RAY DIFFRACTIONc_mcbond_it1.341.5
X-RAY DIFFRACTIONc_mcangle_it2.12
X-RAY DIFFRACTIONc_scbond_it2.142
X-RAY DIFFRACTIONc_scangle_it3.172.5
LS refinement shellResolution: 1.94→2.03 Å / Rfactor Rfree error: 0.016 / Total num. of bins used: 8
RfactorNum. reflection% reflection
Rfree0.234 210 4.9 %
Rwork0.218 4100 -
all-4310 -
obs--86.5 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PROTEIN_REP.PARAMPROTEIN.TOP
X-RAY DIFFRACTION2DNA-RNA_REP.PARAMDNA-RNA.TOP
X-RAY DIFFRACTION3WATER_REP.PARAMWATER.TOP
X-RAY DIFFRACTION4ION.PARAMION.TOP
X-RAY DIFFRACTION51GG.PAR1GG.TOP

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