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- PDB-1qj7: Novel Covalent Active Site Thrombin Inhibitors -

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Basic information

Entry
Database: PDB / ID: 1qj7
TitleNovel Covalent Active Site Thrombin Inhibitors
Components
  • (THROMBIN) x 2
  • HIRUGEN
KeywordsHYDROLASE/HYDROLASE INHIBITOR / HYDROLASE-HYDROLASE INHIBITOR COMPLEX / BLOOD COAGULATION-INHIBITOR COMPLEX / PROTEINASE / BLOOD COAGULATION / TRYPSIN LIKE PROTEINASE / PROTEASE-INHIBITOR COMPLEX / HYDROLASE- HYDROLASE INHIBITOR COMPLEX
Function / homology
Function and homology information


negative regulation of serine-type peptidase activity / positive regulation of lipid kinase activity / cytolysis by host of symbiont cells / positive regulation of phospholipase C-activating G protein-coupled receptor signaling pathway / thrombospondin receptor activity / Defective factor XII causes hereditary angioedema / thrombin / regulation of blood coagulation / neutrophil-mediated killing of gram-negative bacterium / ligand-gated ion channel signaling pathway ...negative regulation of serine-type peptidase activity / positive regulation of lipid kinase activity / cytolysis by host of symbiont cells / positive regulation of phospholipase C-activating G protein-coupled receptor signaling pathway / thrombospondin receptor activity / Defective factor XII causes hereditary angioedema / thrombin / regulation of blood coagulation / neutrophil-mediated killing of gram-negative bacterium / ligand-gated ion channel signaling pathway / Defective F8 cleavage by thrombin / Platelet Aggregation (Plug Formation) / negative regulation of astrocyte differentiation / negative regulation of platelet activation / positive regulation of collagen biosynthetic process / negative regulation of cytokine production involved in inflammatory response / positive regulation of blood coagulation / negative regulation of fibrinolysis / Gamma-carboxylation of protein precursors / Transport of gamma-carboxylated protein precursors from the endoplasmic reticulum to the Golgi apparatus / Common Pathway of Fibrin Clot Formation / Removal of aminoterminal propeptides from gamma-carboxylated proteins / fibrinolysis / regulation of cytosolic calcium ion concentration / Intrinsic Pathway of Fibrin Clot Formation / Peptide ligand-binding receptors / positive regulation of release of sequestered calcium ion into cytosol / acute-phase response / Regulation of Complement cascade / negative regulation of proteolysis / Cell surface interactions at the vascular wall / lipopolysaccharide binding / positive regulation of receptor signaling pathway via JAK-STAT / growth factor activity / serine-type endopeptidase inhibitor activity / positive regulation of insulin secretion / platelet activation / response to wounding / positive regulation of protein localization to nucleus / Golgi lumen / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / positive regulation of reactive oxygen species metabolic process / blood coagulation / antimicrobial humoral immune response mediated by antimicrobial peptide / Thrombin signalling through proteinase activated receptors (PARs) / heparin binding / regulation of cell shape / positive regulation of cell growth / G alpha (q) signalling events / collagen-containing extracellular matrix / blood microparticle / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / cell surface receptor signaling pathway / positive regulation of protein phosphorylation / G protein-coupled receptor signaling pathway / endoplasmic reticulum lumen / serine-type endopeptidase activity / signaling receptor binding / positive regulation of cell population proliferation / calcium ion binding / proteolysis / extracellular space / extracellular exosome / extracellular region / plasma membrane
Similarity search - Function
Hirudin / Proteinase inhibitor I14, hirudin / Thrombin inhibitor hirudin / Hirudin/antistatin / Prothrombin/thrombin / Thrombin light chain / Thrombin light chain domain superfamily / : / Thrombin light chain / Kringle domain ...Hirudin / Proteinase inhibitor I14, hirudin / Thrombin inhibitor hirudin / Hirudin/antistatin / Prothrombin/thrombin / Thrombin light chain / Thrombin light chain domain superfamily / : / Thrombin light chain / Kringle domain / Kringle / Kringle, conserved site / Kringle superfamily / Kringle domain signature. / Kringle domain profile. / Kringle 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. / 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 family, serine active site. / Serine proteases, trypsin domain profile. / 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-GR1 / Prothrombin / Hirudin variant-1 / Hirudin variant-1
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
HIRUDO MEDICINALIS (medicinal leech)
MethodX-RAY DIFFRACTION / OTHER / Resolution: 2.2 Å
AuthorsJhoti, H. / Cleasby, A.
CitationJournal: Biochemistry / Year: 1999
Title: Crystal Structures of Thrombin Complexed to a Novel Series of Synthetic Inhibitors Containing a 5,5-Trans-Lactone Template
Authors: Jhoti, H. / Cleasby, A. / Reid, S. / Thomas, P. / Weir, M. / Wonacott, A.
History
DepositionJun 22, 1999Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 22, 2000Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Atomic model / Database references ...Atomic model / Database references / Derived calculations / Non-polymer description / Structure summary / Version format compliance
Revision 1.2Nov 30, 2012Group: Other
Revision 1.3Mar 13, 2013Group: Other
Revision 1.4Jul 12, 2017Group: Refinement description / Category: software / Item: _software.name
Revision 1.5May 30, 2018Group: Data collection / Structure summary / Category: struct / Item: _struct.title

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: THROMBIN
B: THROMBIN
I: HIRUGEN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,7064
Polymers35,2403
Non-polymers4661
Water3,747208
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4450 Å2
ΔGint-26 kcal/mol
Surface area16410 Å2
MethodPQS
Unit cell
Length a, b, c (Å)71.400, 72.100, 72.800
Angle α, β, γ (deg.)90.00, 100.70, 90.00
Int Tables number5
Space group name H-MC121

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Components

#1: Protein/peptide THROMBIN / FACTOR II


Mass: 4096.534 Da / Num. of mol.: 1 / Fragment: ALPHA THROMBIN, RESIDUES 328-363 / Source method: isolated from a natural source / Source: (natural) HOMO SAPIENS (human) / Tissue: BLOOD PLASMA / References: UniProt: P00734, thrombin
#2: Protein THROMBIN / FACTOR II


Mass: 29780.219 Da / Num. of mol.: 1 / Fragment: ALPHA THROMBIN, RESIDUES 364-622 / Source method: isolated from a natural source / Source: (natural) HOMO SAPIENS (human) / Tissue: BLOOD PLASMA / References: UniProt: P00734, thrombin
#3: Protein/peptide HIRUGEN


Mass: 1363.399 Da / Num. of mol.: 1 / Fragment: PEPTIDE FRAGMENT OF HIRUDIN / Source method: obtained synthetically / Details: EXOSITE INHIBITOR OF THROMBIN / Source: (synth.) HIRUDO MEDICINALIS (medicinal leech) / References: UniProt: P28501, UniProt: P01050*PLUS
#4: Chemical ChemComp-GR1 / 6-CARBAMIMIDOYL-2-[5-(3-DIETHYLCARBAMOYL-PHENYL)-2-HYDROXY-INDAN-1-YL]-HEXANOIC ACID / GR179849


Mass: 465.585 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H35N3O4
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 208 / Source method: isolated from a natural source / Formula: H2O
Compound detailsTHE THROMBIN NUMBERING SYSTEM USED IN THE X-RAY STRUCTURE IS THE CONVENTION FOR CHYMOTRYPSIN.

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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: 2.61 Å3/Da / Density % sol: 52.92 %
Crystal growpH: 7
Details: CRYSTALS WERE GROWN BY MACROSEEDING A SOLUTION OF 100MM HEPES PH 7.0, 22% PEG4K, 200MM NACL. PROTEIN CONCENTRATION OF 5MG/ML.
Crystal grow
*PLUS
pH: 7.3 / Method: vapor diffusion, hanging drop / Details: Skrzypczak, J., (1991) J. Mol. Biol., 221, 1379.
Components of the solutions
*PLUS
IDConc.Common nameCrystal-IDSol-IDChemical formula
13.0-3.7 mg/mlprotein1drop
20.05 Msodium phosphate1drop
30.375 M1dropNaCl
40.5 mM1dropNaN3
50.1 Msodium phosphate1reservoir
61-2 mM1reservoirNaN3
725-30 %(w/v)PEG80001reservoir

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Data collection

DiffractionMean temperature: 290 K
Diffraction sourceSource: ROTATING ANODE / Type: ENRAF / Wavelength: 1.5418
DetectorType: BRUKER NONIUS / Detector: AREA DETECTOR / Details: MONOCHROMATOR
RadiationMonochromator: GRAPHITE(002) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.2→30 Å / Num. obs: 18523 / % possible obs: 98 % / Redundancy: 2.3 % / Rsym value: 0.059
Reflection
*PLUS
Rmerge(I) obs: 0.059

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Processing

Software
NameVersionClassification
X-PLOR3.1refinement
MADNESSdata reduction
CCP4data scaling
X-PLOR3.1phasing
RefinementMethod to determine structure: OTHER / Resolution: 2.2→15 Å / Data cutoff high absF: 10000000 / Data cutoff low absF: 0.001 / Isotropic thermal model: RESTRAINED / σ(F): 2
RfactorNum. reflection% reflection
Rwork0.187 --
obs0.187 18523 98 %
Refinement stepCycle: LAST / Resolution: 2.2→15 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2474 0 33 208 2715
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONx_bond_d0.019
X-RAY DIFFRACTIONx_bond_d_na
X-RAY DIFFRACTIONx_bond_d_prot
X-RAY DIFFRACTIONx_angle_d
X-RAY DIFFRACTIONx_angle_d_na
X-RAY DIFFRACTIONx_angle_d_prot
X-RAY DIFFRACTIONx_angle_deg3
X-RAY DIFFRACTIONx_angle_deg_na
X-RAY DIFFRACTIONx_angle_deg_prot
X-RAY DIFFRACTIONx_dihedral_angle_d
X-RAY DIFFRACTIONx_dihedral_angle_d_na
X-RAY DIFFRACTIONx_dihedral_angle_d_prot
X-RAY DIFFRACTIONx_improper_angle_d
X-RAY DIFFRACTIONx_improper_angle_d_na
X-RAY DIFFRACTIONx_improper_angle_d_prot
X-RAY DIFFRACTIONx_mcbond_it
X-RAY DIFFRACTIONx_mcangle_it
X-RAY DIFFRACTIONx_scbond_it
X-RAY DIFFRACTIONx_scangle_it
Software
*PLUS
Name: X-PLOR / Version: 3.1 / Classification: refinement
Refinement
*PLUS
Solvent computation
*PLUS
Displacement parameters
*PLUS
Biso mean: 33.5 Å2

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