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- PDB-1a4w: CRYSTAL STRUCTURES OF THROMBIN WITH THIAZOLE-CONTAINING INHIBITOR... -

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Basic information

Entry
Database: PDB / ID: 1a4w
TitleCRYSTAL STRUCTURES OF THROMBIN WITH THIAZOLE-CONTAINING INHIBITORS: PROBES OF THE S1' BINDING SITE
Components
  • (ALPHA-THROMBIN ...) x 2
  • HIRUGEN
KeywordsHYDROLASE/HYDROLASE INHIBITOR / SERINE PROTEASE-INHIBITOR / BLOOD COAGULATION / 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 / regulation of blood coagulation / cytolysis by host of symbiont cells / thrombospondin receptor activity / negative regulation of astrocyte differentiation / neutrophil mediated killing of gram-negative bacterium / thrombin / negative regulation of cytokine production involved in inflammatory response / negative regulation of platelet activation ...positive regulation of lipid kinase activity / positive regulation of phospholipase C-activating G protein-coupled receptor signaling pathway / regulation of blood coagulation / cytolysis by host of symbiont cells / thrombospondin receptor activity / negative regulation of astrocyte differentiation / neutrophil mediated killing of gram-negative bacterium / thrombin / negative regulation of cytokine production involved in inflammatory response / negative regulation of platelet activation / negative regulation of fibrinolysis / positive regulation of collagen biosynthetic process / positive regulation of blood coagulation / blood coagulation, intrinsic pathway / regulation of cytosolic calcium ion concentration / enzyme activator activity / positive regulation of receptor signaling pathway via JAK-STAT / positive regulation of release of sequestered calcium ion into cytosol / fibrinolysis / lipopolysaccharide binding / regulation of complement activation / acute-phase response / negative regulation of proteolysis / response to wounding / positive regulation of protein localization to nucleus / growth factor activity / positive regulation of reactive oxygen species metabolic process / serine-type endopeptidase inhibitor activity / Golgi lumen / platelet activation / endoplasmic reticulum to Golgi vesicle-mediated transport / leukocyte migration / positive regulation of phosphatidylinositol 3-kinase signaling / heparin binding / positive regulation of cell growth / regulation of cell shape / regulation of gene expression / cell surface receptor signaling pathway / blood microparticle / antimicrobial humoral immune response mediated by antimicrobial peptide / multicellular organism development / blood coagulation / positive regulation of protein phosphorylation / G protein-coupled receptor signaling pathway / endoplasmic reticulum lumen / signaling receptor binding / proteolysis / serine-type endopeptidase activity / cellular protein metabolic process / positive regulation of cell population proliferation / calcium ion binding / cell / extracellular space / extracellular exosome / extracellular region / plasma membrane
Peptidase S1, PA clan / Hirudin/antistatin / Kringle / Gamma-carboxyglutamic acid-rich (GLA) domain / Proteinase inhibitor I14, hirudin / Serine proteases, trypsin domain / Peptidase S1A, chymotrypsin family / Prothrombin/thrombin / Kringle-like fold / Kringle, conserved site ...Peptidase S1, PA clan / Hirudin/antistatin / Kringle / Gamma-carboxyglutamic acid-rich (GLA) domain / Proteinase inhibitor I14, hirudin / Serine proteases, trypsin domain / Peptidase S1A, chymotrypsin family / Prothrombin/thrombin / Kringle-like fold / Kringle, conserved site / Serine proteases, trypsin family, histidine active site / Thrombin light chain / Serine proteases, trypsin family, serine active site / Gamma-carboxyglutamic acid-rich (GLA) domain superfamily / Thrombin light chain domain superfamily / Kringle superfamily / Trypsin / Trypsin-like serine proteases / Thrombin, subunit H / Beta Barrel / Mainly Beta
Prothrombin / Hirudin variant-2 / RWJ-50215
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / PREVIOUS STRUCTURE / Resolution: 1.8 Å
AuthorsMatthews, J.H. / Krishnan, R. / Costanzo, M.J. / Maryanoff, B.E. / Tulinsky, A.
Citation
Journal: Biophys.J. / Year: 1996
Title: Crystal structures of thrombin with thiazole-containing inhibitors: probes of the S1' binding site.
Authors: Matthews, J.H. / Krishnan, R. / Costanzo, M.J. / Maryanoff, B.E. / Tulinsky, A.
#1: Journal: Protein Sci. / Year: 1994
Title: The Isomorphous Structures of Prethrombin2, Hirugen-, and Ppack-Thrombin: Changes Accompanying Activation and Exosite Binding to Thrombin
Authors: Vijayalakshmi, J. / Padmanabhan, K.P. / Mann, K.G. / Tulinsky, A.
#2: Journal: Blood Coagulation Fibrinolysis / Year: 1993
Title: Active Site and Exosite Binding of Alpha-Thrombin
Authors: Tulinsky, A. / Qiu, X.
#3: Journal: Biochemistry / Year: 1992
Title: Structure of the Hirulog 3-Thrombin Complex and Nature of the S' Subsites of Substrates and Inhibitors
Authors: Qiu, X. / Padmanabhan, K.P. / Carperos, V.E. / Tulinsky, A. / Kline, T. / Maraganore, J.M. / Fenton II, J.W.
Validation Report
SummaryFull reportAbout validation report
History
DepositionFeb 6, 1998-
Revision 1.0Apr 29, 1998Provider: repository / Type: Initial release
Revision 1.1Mar 24, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Atomic model / Database references ...Atomic model / Database references / Derived calculations / Non-polymer description / Structure summary / Version format compliance
Revision 1.3Dec 12, 2012Group: Other

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
L: ALPHA-THROMBIN (SMALL SUBUNIT)
H: ALPHA-THROMBIN (LARGE SUBUNIT)
I: HIRUGEN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,0726
Polymers35,4113
Non-polymers6613
Water2,828157
1


TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
γ
α
β
Length a, b, c (Å)71.470, 72.000, 73.390
Angle α, β, γ (deg.)90.00, 101.13, 90.00
Int Tables number5
Space group name H-MC121

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Components

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ALPHA-THROMBIN ... , 2 types, 2 molecules LH

#1: Protein/peptide ALPHA-THROMBIN (SMALL SUBUNIT)


Mass: 4096.534 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / Organ: BLOOD / Tissue: BLOOD / References: UniProt: P00734, thrombin
#2: Protein/peptide ALPHA-THROMBIN (LARGE SUBUNIT)


Mass: 29780.219 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / Organ: BLOOD / Tissue: BLOOD / References: UniProt: P00734, thrombin

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Protein/peptide , 1 types, 1 molecules I

#3: Protein/peptide HIRUGEN


Mass: 1534.554 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
References: UniProt: P09945

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Non-polymers , 3 types, 160 molecules

#4: Chemical ChemComp-NA / SODIUM ION / Sodium


Mass: 22.990 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Na
#5: Chemical ChemComp-QWE / amino{[(4S)-4-({[5-(dimethylamino)naphthalen-1-yl]sulfonyl}amino)-5-oxo-5-{(2R)-2-[3-oxo-3-(1,3-thiazol-2-yl)propyl]piperidin-1-yl}pentyl]amino}methaniminium / RWJ-50215


Mass: 614.802 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H40N7O4S2 / References: RWJ-50215
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 157 / Source method: isolated from a natural source / Formula: H2O

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Details

Compound detailsTHROMBIN IS CLEAVED BETWEEN RESIDUES 15 AND 16. CHAIN IDENTIFIER *L* IS USED FOR RESIDUES 1H - 15 ...THROMBIN IS CLEAVED BETWEEN RESIDUES 15 AND 16. CHAIN IDENTIFIER *L* IS USED FOR RESIDUES 1H - 15 AND CHAIN IDENTIFIER *H* IS USED FOR RESIDUES 16 - 247. CHAIN IDENTIFIER *I* IS USED FOR HIRUGEN, THE CARBOXYL.

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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: 2.4 Å3/Da / Density % sol: 51 %
Crystal growMethod: vapor diffusion - hanging drop, macroseeding / pH: 7.3
Details: 0.1 M SODIUM PHOSPHATE BUFFER AT PH 7.3, 27-28% PEG 8000; HANGING DROPS WITH MACROSEEDING, vapor diffusion - hanging drop and macroseeding
Crystal grow
*PLUS
Method: vapor diffusion, hanging drop / Details: Skrzypczak, J., (1991) J. Mol. Biol., 221, 1379.
Components of the solutions
*PLUS

Crystal-ID: 1

IDConc.Common nameSol-IDChemical formula
13.0-3.7 mg/mlproteindrop
20.05 Msodium phosphatedrop
30.375 MdropNaCl
40.5 mMdropNaN3
50.1 Msodium phospahtereservoir
61-2 mMreservoirNaN3
725-30 %(v/v)PEG8000reservoir

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Data collection

DiffractionMean temperature: 298 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RUH2R / Wavelength: 1.5418
DetectorType: RIGAKU RAXIS II / Detector: IMAGE PLATE / Date: Mar 15, 1994 / Details: COLLIMATOR
RadiationMonochromator: GRAPHITE(002) / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.8→44.2 Å / Num. obs: 23968 / % possible obs: 69.5 % / Observed criterion σ(I): 1 / Redundancy: 2.2 % / Rmerge(I) obs: 0.052 / Net I/σ(I): 12
Reflection shellResolution: 1.8→2 Å / Rmerge(I) obs: 0.165 / Mean I/σ(I) obs: 2.61 / % possible all: 48
Reflection
*PLUS
Num. measured all: 52463

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Processing

Software
NameClassification
R-AXISdata collection
R-AXISdata reduction
PROFFTrefinement
R-AXISdata scaling
RefinementMethod to determine structure: PREVIOUS STRUCTURE
Starting model: PDB ENTRY 1FPC
Resolution: 1.8→7 Å / σ(F): 4
RfactorNum. reflection% reflection
Rwork0.155 --
Obs-19906 65 %
Displacement parametersBiso mean: 26 Å2
Refinement stepCycle: LAST / Resolution: 1.8→7 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2238 0 44 157 2439
Refine LS restraints

Refinement-ID: X-RAY DIFFRACTION

TypeDev idealDev ideal target
p_bond_d0.0160.015
p_angle_d0.0420.03
p_angle_deg
p_planar_d0.0510.045
p_hb_or_metal_coord
p_mcbond_it1.11
p_mcangle_it1.81.5
p_scbond_it2.82
p_scangle_it4.12.5
p_plane_restr0.0320.03
p_chiral_restr0.210.15
p_singtor_nbd0.190.6
p_multtor_nbd0.210.6
p_xhyhbond_nbd
p_xyhbond_nbd0.250.6
p_planar_tor43
p_staggered_tor2015
p_orthonormal_tor
p_transverse_tor3020
p_special_tor
Software
*PLUS
Name: PROFFT / Classification: refinement
Refinement
*PLUS
Rfactor obs: 0.155

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