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- PDB-4rn6: Structure of prethrombin-2 mutant s195a bound to the active site ... -

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Basic information

Entry
Database: PDB / ID: 4rn6
TitleStructure of prethrombin-2 mutant s195a bound to the active site inhibitor argatroban
ComponentsThrombin heavy chain
KeywordsHYDROLASE/HYDROLASE INHIBITOR / SERINE PROTEASE / PRETHROMBIN-2 / AUTOACTIVATION / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


positive regulation of lipid kinase activity / positive regulation of phospholipase C-activating G protein-coupled receptor signaling pathway / thrombospondin receptor activity / Defective factor XII causes hereditary angioedema / neutrophil-mediated killing of gram-negative bacterium / regulation of blood coagulation / cytolysis by host of symbiont cells / thrombin / Defective F8 cleavage by thrombin / Platelet Aggregation (Plug Formation) ...positive regulation of lipid kinase activity / positive regulation of phospholipase C-activating G protein-coupled receptor signaling pathway / thrombospondin receptor activity / Defective factor XII causes hereditary angioedema / neutrophil-mediated killing of gram-negative bacterium / regulation of blood coagulation / cytolysis by host of symbiont cells / thrombin / Defective F8 cleavage by thrombin / Platelet Aggregation (Plug Formation) / negative regulation of astrocyte differentiation / negative regulation of fibrinolysis / negative regulation of cytokine production involved in inflammatory response / negative regulation of platelet activation / positive regulation of collagen biosynthetic process / positive regulation of blood coagulation / Transport of gamma-carboxylated protein precursors from the endoplasmic reticulum to the Golgi apparatus / Gamma-carboxylation of protein precursors / Peptide ligand-binding receptors / Common Pathway of Fibrin Clot Formation / Removal of aminoterminal propeptides from gamma-carboxylated proteins / regulation of cytosolic calcium ion concentration / positive regulation of receptor signaling pathway via JAK-STAT / positive regulation of release of sequestered calcium ion into cytosol / Intrinsic Pathway of Fibrin Clot Formation / fibrinolysis / Thrombin signalling through proteinase activated receptors (PARs) / lipopolysaccharide binding / Regulation of Complement cascade / acute-phase response / Cell surface interactions at the vascular wall / negative regulation of proteolysis / growth factor activity / response to wounding / positive regulation of protein localization to nucleus / platelet activation / G alpha (q) signalling events / Golgi lumen / multicellular organism development / positive regulation of reactive oxygen species metabolic process / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / blood coagulation / positive regulation of phosphatidylinositol 3-kinase signaling / heparin binding / positive regulation of cell growth / collagen-containing extracellular matrix / regulation of cell shape / blood microparticle / cell surface receptor signaling pathway / antimicrobial humoral immune response mediated by antimicrobial peptide / positive regulation of protein phosphorylation / proteolysis / signaling receptor binding / serine-type endopeptidase activity / endoplasmic reticulum lumen / calcium ion binding / positive regulation of cell population proliferation / extracellular space / extracellular exosome / extracellular region / plasma membrane
Similarity search - Function
Thrombin light chain domain superfamily / Thrombin light chain / Prothrombin/thrombin / Thrombin light chain / Kringle domain / Kringle domain profile. / Kringle superfamily / Kringle, conserved site / Kringle domain signature. / Kringle ...Thrombin light chain domain superfamily / Thrombin light chain / Prothrombin/thrombin / Thrombin light chain / Kringle domain / Kringle domain profile. / Kringle superfamily / Kringle, conserved site / Kringle domain signature. / Kringle / Kringle domain / Vitamin K-dependent carboxylation/gamma-carboxyglutamic (GLA) domain / Domain containing Gla (gamma-carboxyglutamate) residues. / Gamma-carboxyglutamic acid-rich (GLA) domain superfamily / Gla domain profile. / Vitamin K-dependent carboxylation domain. / Gamma-carboxyglutamic acid-rich (GLA) domain / Kringle-like fold / 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
S-argatroban / Chem-15U / Prothrombin
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 3 Å
AuthorsPozzi, N. / Chen, Z. / Zapata, F. / Niu, W. / Barranco-Medina, S. / Pelc, L.A. / Di Cera, E.
Citation
Journal: J.Biol.Chem. / Year: 2013
Title: Autoactivation of thrombin precursors.
Authors: Pozzi, N. / Chen, Z. / Zapata, F. / Niu, W. / Barranco-Medina, S. / Pelc, L.A. / Di Cera, E.
#1: Journal: Biochemistry / Year: 2011
Title: Crystal structures of prethrombin-2 reveal alternative conformations under identical solution conditions and the mechanism of zymogen activation.
Authors: Pozzi, N. / Chen, Z. / Zapata, F. / Pelc, L.A. / Barranco-Medina, S. / Di Cera, E.
History
DepositionOct 23, 2014Deposition site: RCSB / Processing site: RCSB
SupersessionNov 5, 2014ID: 4HFY
Revision 1.0Nov 5, 2014Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Thrombin heavy chain
B: Thrombin heavy chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)67,8044
Polymers66,7872
Non-polymers1,0172
Water0
1
A: Thrombin heavy chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,9022
Polymers33,3931
Non-polymers5091
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Thrombin heavy chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,9022
Polymers33,3931
Non-polymers5091
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
γ
α
β
Length a, b, c (Å)43.919, 81.840, 77.761
Angle α, β, γ (deg.)90.00, 100.62, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Thrombin heavy chain /


Mass: 33393.270 Da / Num. of mol.: 2 / Fragment: UNP residues 333-622 / Mutation: S195A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: F2 / Production host: Escherichia coli (E. coli) / References: UniProt: P00734, thrombin
#2: Chemical ChemComp-15U / (2R,4R)-4-methyl-1-(N~2~-{[(3S)-3-methyl-1,2,3,4-tetrahydroquinolin-8-yl]sulfonyl}-L-arginyl)piperidine-2-carboxylic acid / S-argatroban


Type: peptide-like, Peptide-like / Class: Inhibitor / Mass: 508.634 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H36N6O5S / References: S-argatroban

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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: 2.06 Å3/Da / Density % sol: 40.19 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / pH: 8.5
Details: 100 mM TRIS PH 8.5, 200 mM LI2SO4 AND 30% PEG 3000, VAPOR DIFFUSION, HANGING DROP, TEMPERATURE 295K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: Apr 22, 2012
RadiationMonochromator: MIRROR / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 3→32.13 Å / Num. all: 11154 / Num. obs: 10552 / % possible obs: 94.6 % / Observed criterion σ(F): -1 / Observed criterion σ(I): -1 / Redundancy: 3.5 % / Rmerge(I) obs: 0.156 / Net I/σ(I): 5.9
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique allDiffraction-ID% possible all
3-3.052.40.4472493189.8
3.05-3.112.50.4212.1495190
3.11-3.172.60.3882.3498192.1
3.17-3.232.80.3792.5539193.4
3.23-3.32.80.3362.9498193.6
3.3-3.382.90.3273528193.8

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Processing

Software
NameVersionClassification
CrystalCleardata collection
MOLREPFROM CCP4phasing
REFMAC5.5.0109refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3SQH
Resolution: 3→32.13 Å / Cross valid method: THROUGHOUT / σ(F): -1 / σ(I): -1 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.343 477 4.6 %RANDOM
Rwork0.248 ---
obs0.252 9833 94.3 %-
all-10427 --
Displacement parametersBiso mean: 30.03 Å2
Baniso -1Baniso -2Baniso -3
1--0.07 Å20 Å2-0.01 Å2
2--0 Å20 Å2
3---0.07 Å2
Refinement stepCycle: LAST / Resolution: 3→32.13 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4610 0 70 0 4680
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONr_bond_refined_d0.007
X-RAY DIFFRACTIONr_angle_refined_deg1.105
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.79
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.181
X-RAY DIFFRACTIONr_dihedral_angle_3_deg20.336
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.547
X-RAY DIFFRACTIONr_chiral_restr0.078
X-RAY DIFFRACTIONr_gen_planes_refined0.004
X-RAY DIFFRACTIONr_mcbond_it0.273
X-RAY DIFFRACTIONr_mcangle_it0.508
X-RAY DIFFRACTIONr_scbond_it0.499
X-RAY DIFFRACTIONr_scangle_it0.876
LS refinement shellResolution: 3→3.08 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.452 27 -
Rwork0.301 --
obs-659 86.51 %

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