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- PDB-4x8t: FACTOR VIIA IN COMPLEX WITH THE INHIBITOR 7-chloro-3,4-dihydroiso... -

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Basic information

Entry
Database: PDB / ID: 4x8t
TitleFACTOR VIIA IN COMPLEX WITH THE INHIBITOR 7-chloro-3,4-dihydroisoquinolin-1(2H)-one
Components
  • Factor VIIa (Heavy Chain)
  • Factor VIIa (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 / positive regulation of leukocyte chemotaxis / response to cholesterol / response to growth hormone / positive regulation of positive chemotaxis / Extrinsic Pathway of Fibrin Clot Formation / 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 / signaling receptor binding / serine-type endopeptidase activity / 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 / 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. ...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 / 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
7-chloro-3,4-dihydroisoquinolin-1(2H)-one / Coagulation factor VII
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsWei, A.
CitationJournal: J.Med.Chem. / Year: 2015
Title: Discovery of Novel P1 Groups for Coagulation Factor VIIa Inhibition Using Fragment-Based Screening.
Authors: Cheney, D.L. / Bozarth, J.M. / Metzler, W.J. / Morin, P.E. / Mueller, L. / Newitt, J.A. / Nirschl, A.H. / Rendina, A.R. / Tamura, J.K. / Wei, A. / Wen, X. / Wurtz, N.R. / Seiffert, D.A. / ...Authors: Cheney, D.L. / Bozarth, J.M. / Metzler, W.J. / Morin, P.E. / Mueller, L. / Newitt, J.A. / Nirschl, A.H. / Rendina, A.R. / Tamura, J.K. / Wei, A. / Wen, X. / Wurtz, N.R. / Seiffert, D.A. / Wexler, R.R. / Priestley, E.S.
History
DepositionDec 10, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 25, 2015Provider: repository / Type: Initial release
Revision 1.1Apr 8, 2015Group: Database references

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
H: Factor VIIa (Heavy Chain)
L: Factor VIIa (Light Chain)
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,7368
Polymers34,1342
Non-polymers6026
Water2,576143
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3000 Å2
ΔGint-72 kcal/mol
Surface area13040 Å2
MethodPISA
Unit cell
Length a, b, c (Å)94.480, 94.480, 108.090
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number92
Space group name H-MP41212
Detailschains H & L

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Components

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Protein , 2 types, 2 molecules HL

#1: Protein Factor VIIa (Heavy Chain) / Proconvertin / Serum prothrombin conversion accelerator / SPCA


Mass: 28103.256 Da / Num. of mol.: 1 / Fragment: unp RESIDUES 213-466
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 VIIa (Light Chain) / Proconvertin / Serum prothrombin conversion accelerator / SPCA


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

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Non-polymers , 5 types, 149 molecules

#3: Chemical ChemComp-3Z8 / 7-chloro-3,4-dihydroisoquinolin-1(2H)-one


Mass: 181.619 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C9H8ClNO
#4: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Ca
#5: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#6: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#7: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 143 / 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: 3.53 Å3/Da / Density % sol: 65.19 %
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

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Jul 14, 2006
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.2→50 Å / Num. obs: 24396 / % possible obs: 95.1 % / Observed criterion σ(I): 0 / Redundancy: 7.3 % / Biso Wilson estimate: 39.07 Å2 / Rmerge(I) obs: 0.093 / Net I/σ(I): 23.6
Reflection shellResolution: 2.2→2.28 Å / Redundancy: 6.9 % / Rmerge(I) obs: 0.48 / Mean I/σ(I) obs: 3.9 / Rejects: 0 / % possible all: 96.3

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Processing

Software
NameVersionClassification
BUSTER-TNTBUSTER 2.11.5refinement
PDB_EXTRACT3.15data extraction
HKL-2000data reduction
HKL-2000data scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: FACTOR VIIA/LIGAND

Resolution: 2.2→33.29 Å / Cor.coef. Fo:Fc: 0.929 / Cor.coef. Fo:Fc free: 0.9157 / SU R Cruickshank DPI: 0.208 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.22 / SU Rfree Blow DPI: 0.176 / SU Rfree Cruickshank DPI: 0.172
RfactorNum. reflection% reflectionSelection details
Rfree0.2212 2163 9.86 %RANDOM
Rwork0.1978 ---
obs0.2001 21947 86.23 %-
Displacement parametersBiso max: 126.86 Å2 / Biso mean: 39.71 Å2 / Biso min: 19.57 Å2
Baniso -1Baniso -2Baniso -3
1-4.9955 Å20 Å20 Å2
2--4.9955 Å20 Å2
3----9.9909 Å2
Refine analyzeLuzzati coordinate error obs: 0.295 Å
Refinement stepCycle: final / Resolution: 2.2→33.29 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2320 0 34 143 2497
Biso mean--65.83 39.74 -
Num. residues----305
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d794SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes45HARMONIC2
X-RAY DIFFRACTIONt_gen_planes371HARMONIC5
X-RAY DIFFRACTIONt_it2428HARMONIC20
X-RAY DIFFRACTIONt_nbd0SEMIHARMONIC5
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion309SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact2853SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2428HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg3320HARMONIC21.1
X-RAY DIFFRACTIONt_omega_torsion3.61
X-RAY DIFFRACTIONt_other_torsion16.45
LS refinement shellResolution: 2.2→2.31 Å / Total num. of bins used: 11
RfactorNum. reflection% reflection
Rfree0.3891 220 9.72 %
Rwork0.3383 2043 -
all0.3432 2263 -
obs--86.23 %

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