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- PDB-1a5g: HUMAN THROMBIN COMPLEXED WITH NOVEL SYNTHETIC PEPTIDE MIMETIC INH... -

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Basic information

Entry
Database: PDB / ID: 1a5g
TitleHUMAN THROMBIN COMPLEXED WITH NOVEL SYNTHETIC PEPTIDE MIMETIC INHIBITOR AND HIRUGEN
Components
  • (ALPHA-THROMBIN ...) x 2
  • HIRUGEN
KeywordsHYDROLASE/HYDROLASE INHIBITOR / COMPLEX (SERINE PROTEASE-INHIBITOR) / 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 / MOL-126
Biological speciesHomo sapiens (human)
Hirudo medicinalis (medicinal leech)
MethodX-RAY DIFFRACTION / Resolution: 2.06 Å
AuthorsSt Charles, R. / Tulinsky, A. / Kahn, M.
Citation
Journal: J.Med.Chem. / Year: 1999
Title: Bound structures of novel P3-P1' beta-strand mimetic inhibitors of thrombin.
Authors: St Charles, R. / Matthews, J.H. / Zhang, E. / Tulinsky, A.
#1: Journal: Protein Eng. / Year: 1993
Title: The Structure of a Designed Peptidomimetic Inhibitor Complex of Alpha-Thrombin
Authors: Wu, T.P. / Yee, V. / Tulinsky, A. / Chrusciel, R.A. / Nakanishi, H. / Shen, R. / Priebe, C. / Kahn, M.
#2: Journal: Blood Coagulation Fibrinolysis / Year: 1993
Title: Active Site and Exosite Binding of Alpha-Thrombin
Authors: Tulinsky, A. / Qiu, X.
Validation Report
SummaryFull reportAbout validation report
History
DepositionFeb 16, 1998-
Revision 1.0May 27, 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)36,0366
Polymers35,4113
Non-polymers6253
Water2,432135
1


TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
γ
α
β
Length a, b, c (Å)70.810, 72.250, 72.790
Angle α, β, γ (deg.)90.00, 100.80, 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 natural source / Source: (natural) Hirudo medicinalis (medicinal leech) / References: UniProt: P09945

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Non-polymers , 3 types, 138 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-00L / (1S,7S)-7-amino-7-benzyl-N-[(1S)-4-carbamimidamido-1-{(1S)-1-hydroxy-2-oxo-2-[(2-phenylethyl)amino]ethyl}butyl]-8-oxohexahydro-1H-pyrazolo[1,2-a]pyridazine-1-carboxamide / MOL-126


Mass: 578.706 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C30H42N8O4 / References: MOL-126
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 135 / 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 TERMINUS OF HIRUDIN, WHICH OCCUPIES THE EXOSITE. THE INHIBITOR 00L IS COVALENTLY CONNECTED TO SER 195 OF THE ENZYME TO FORM A HEMIKETAL.

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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: 2.6 Å3/Da / Density % sol: 49 %
Crystal growpH: 7.3
Details: PROTEIN WAS CRYSTALLIZED FROM 15% PEG 8000, 75 MM NAPO4, PH 7.3, 187 MM NACL, 1 MM NAN3; THEN SOAKED IN 7 MM INHIBITOR.
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 phosphatereservoir
61-2 mMreservoirNaN3
725-30 %(v/v)PEG8000reservoir

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Data collection

DiffractionMean temperature: 273 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RUH2R / Wavelength: 1.5418
DetectorType: RIGAKU / Detector: IMAGE PLATE / Date: Oct 15, 1996
RadiationMonochromator: NI FILTER / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionHighest resolution: 2.1 Å / Num. obs: 18339 / % possible obs: 81 % / Observed criterion σ(I): 2 / Redundancy: 2.1 % / Rmerge(I) obs: 0.072

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Processing

Software
NameVersionClassification
R-AXISIIdata collection
R-AXISIIdata reduction
PROFFTrefinement
R-AXISIIdata scaling
RefinementResolution: 2.06→7 Å / σ(F): 4
RfactorNum. reflection% reflection
Rwork0.158 --
Obs-14977 81 %
Displacement parametersBiso mean: 30 Å2
Refinement stepCycle: LAST / Resolution: 2.06→7 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2334 0 44 135 2513
Refine LS restraints

Refinement-ID: X-RAY DIFFRACTION

TypeDev idealDev ideal target
p_bond_d0.0190.02
p_angle_d0.0430.03
p_angle_deg
p_planar_d0.0530.05
p_hb_or_metal_coord
p_mcbond_it0.91
p_mcangle_it1.61.5
p_scbond_it22
p_scangle_it2.82
p_plane_restr0.0210.025
p_chiral_restr0.20.15
p_singtor_nbd0.220.6
p_multtor_nbd0.260.6
p_xhyhbond_nbd
p_xyhbond_nbd0.270.6
p_planar_tor43
p_staggered_tor2115
p_orthonormal_tor
p_transverse_tor3120
p_special_tor
Software
*PLUS
Name: PROFFT / Classification: refinement
Refinement
*PLUS
Rfactor obs: 0.158

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