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- PDB-1a46: THROMBIN COMPLEXED WITH HIRUGEN AND A BETA-STRAND MIMETIC INHIBITOR -

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Entry
Database: PDB / ID: 1a46
TitleTHROMBIN COMPLEXED WITH HIRUGEN AND A BETA-STRAND MIMETIC INHIBITOR
Components
  • (ALPHA-THROMBIN ...) x 2
  • HIRUGEN
KeywordsHYDROLASE/HYDROLASE INHIBITOR / COMPLEX (SERINE PROTEASE-INHIBITOR) / HYDROLASE-HYDROLASE INHIBITOR COMPLEX
Function / homologySerine proteases, trypsin family, serine active site. / Hirudin/antistatin / Intrinsic Pathway of Fibrin Clot Formation / Gamma-carboxyglutamic acid-rich (GLA) domain superfamily / Serine proteases, trypsin family, serine active site / Thrombin light chain / Serine proteases, trypsin family, histidine active site / Kringle, conserved site / Kringle-like fold / Peptidase S1, PA clan ...Serine proteases, trypsin family, serine active site. / Hirudin/antistatin / Intrinsic Pathway of Fibrin Clot Formation / Gamma-carboxyglutamic acid-rich (GLA) domain superfamily / Serine proteases, trypsin family, serine active site / Thrombin light chain / Serine proteases, trypsin family, histidine active site / Kringle, conserved site / Kringle-like fold / Peptidase S1, PA clan / Kringle superfamily / Prothrombin/thrombin / Peptidase S1A, chymotrypsin family / Serine proteases, trypsin domain / Gla domain profile. / Proteinase inhibitor I14, hirudin / Gamma-carboxyglutamic acid-rich (GLA) domain / Kringle domain profile. / Thrombin light chain domain superfamily / Kringle domain / Serine proteases, trypsin domain profile. / Kringle domain signature. / Regulation of Complement cascade / Platelet Aggregation (Plug Formation) / Serine proteases, trypsin family, histidine active site. / Thrombin signalling through proteinase activated receptors (PARs) / G alpha (q) signalling events / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / Peptide ligand-binding receptors / Cell surface interactions at the vascular wall / Kringle / Trypsin / Removal of aminoterminal propeptides from gamma-carboxylated proteins / Transport of gamma-carboxylated protein precursors from the endoplasmic reticulum to the Golgi apparatus / Vitamin K-dependent carboxylation domain. / Thrombin light chain / Hirudin / Gamma-carboxylation of protein precursors / Vitamin K-dependent carboxylation/gamma-carboxyglutamic (GLA) domain / Common Pathway of Fibrin Clot Formation / regulation of blood coagulation / thrombin / positive regulation of lipid kinase activity / positive regulation of phospholipase C-activating G protein-coupled receptor signaling pathway / cytolysis by host of symbiont cells / thrombospondin receptor activity / neutrophil mediated killing of gram-negative bacterium / negative regulation of platelet activation / negative regulation of cytokine production involved in inflammatory response / negative regulation of fibrinolysis / negative regulation of astrocyte differentiation / positive regulation of collagen biosynthetic process / regulation of cytosolic calcium ion concentration / positive regulation of blood coagulation / blood coagulation, intrinsic pathway / positive regulation of receptor signaling pathway via JAK-STAT / positive regulation of release of sequestered calcium ion into cytosol / enzyme activator activity / fibrinolysis / lipopolysaccharide binding / negative regulation of proteolysis / regulation of complement activation / acute-phase response / positive regulation of protein localization to nucleus / response to wounding / growth factor activity / positive regulation of reactive oxygen species metabolic process / serine-type endopeptidase inhibitor activity / Golgi lumen / endoplasmic reticulum to Golgi vesicle-mediated transport / platelet activation / heparin binding / positive regulation of phosphatidylinositol 3-kinase signaling / positive regulation of cell growth / regulation of cell shape / regulation of gene expression / antimicrobial humoral immune response mediated by antimicrobial peptide / cell surface receptor signaling pathway / multicellular organism development / blood microparticle / blood coagulation / positive regulation of protein phosphorylation / G protein-coupled receptor signaling pathway / endoplasmic reticulum lumen / proteolysis / signaling receptor binding / cellular protein metabolic process / serine-type endopeptidase activity / positive regulation of cell population proliferation / calcium ion binding / extracellular space / extracellular exosome / extracellular region / plasma membrane / Prothrombin / Hirudin variant-2
Function and homology information
Specimen sourceHomo sapiens (human)
Hirudo medicinalis (medicinal leech)
MethodX-RAY DIFFRACTION / PREVIOUS STRUCTURE / 2.12 Å resolution
AuthorsSt Charles, R. / Matthews, J.H. / Zhang, E. / 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: 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.
#2: 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.
#3: 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
DateDeposition: Feb 11, 1998 / Release: May 27, 1998
RevisionDateData content typeGroupProviderType
1.0May 27, 1998Structure modelrepositoryInitial release
1.1Mar 24, 2008Structure modelVersion format compliance
1.2Jul 13, 2011Structure modelAtomic model / Database references / Derived calculations / Non-polymer description / Structure summary / Version format compliance
1.3Dec 12, 2012Structure modelOther

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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)35,9866
Polyers35,4113
Non-polymers5753
Water2,972165
1


TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
γ
α
β
Length a, b, c (Å)71.300, 73.090, 73.820
Angle α, β, γ (deg.)90.00, 101.12, 90.00
Int Tables number5
Space group name H-MC 1 2 1

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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: (natural) Homo sapiens (human) / Genus: Homo / Organ: BLOOD / Tissue: BLOOD / References: UniProt: P00734, thrombin
#2: Protein/peptide ALPHA-THROMBIN (LARGE SUBUNIT)


Mass: 29780.219 Da / Num. of mol.: 1 / Source: (natural) Homo sapiens (human) / Genus: Homo / 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: (natural) Hirudo medicinalis (medicinal leech) / Genus: Hirudo / References: UniProt: P09945

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Non-polymers , 3 types, 168 molecules

#4: Chemical ChemComp-NA / SODIUM ION / MOL 106


Mass: 22.990 Da / Num. of mol.: 2 / Formula: Na / Sodium
#5: Chemical ChemComp-00K / (1S,7S)-7-amino-N-[(2R,3S)-7-amino-1-(cyclohexylamino)-2-hydroxy-1-oxoheptan-3-yl]-7-benzyl-8-oxohexahydro-1H-pyrazolo[1,2-a]pyridazine-1-carboxamide / MOL-106


Mass: 528.687 Da / Num. of mol.: 1 / Formula: C28H44N6O4

about BIRD dictionary

PRD-IDPRD_000617
ClassThrombin inhibitor
NameMOL-106
TypePeptide-like
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 165 / Formula: H2O / Water

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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 00K 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: 2.4 / Density percent sol: 51 %
Crystal growMethod: vapor diffusion - hanging drop, macroseeding / pH: 7.3
Details: 0.1 M SODIUM PHOSPHATE BUFFER, PH 7.3, 27-28 % PEG 8000, HANGING DROPS AND MACROSEEDING; THEN SOAKED IN PEG-PHOSPHATE-0.1 M NACL, AND THE MOL 106 INHIBITOR WAS ADDED IN 3 STEPS WITH FINAL CONC. 7.3 MM, 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
IDConcCommon 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 %(v/v)PEG80001reservoir

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Data collection

DiffractionMean temperature: 298 kelvins
SourceSource: ROTATING ANODE / Type: RIGAKU RUH2R / Wavelength: 1.5418
DetectorType: SIEMENS / Details: COLLIMATOR / Detector: AREA DETECTOR / Collection date: May 15, 1995
RadiationMonochromator: GRAPHITE(002) / Monochromatic or laue m l: M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionD resolution high: 2.12 Å / Number obs: 18219 / Rmerge I obs: 0.044 / NetI over sigmaI: 23.8 / Redundancy: 3 % / Percent possible obs: 86
Reflection shellRmerge I obs: 0.229 / Highest resolution: 2.12 Å / Lowest resolution: 2.26 Å / MeanI over sigI obs: 3.5 / Redundancy: 1.7 % / Percent possible all: 6
Reflection
*PLUS
Number measured all: 54609
Reflection shell
*PLUS
Percent possible obs: 6

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Processing

Software
NameClassification
XENGENdata collection
XENGENdata reduction
PROFFTrefinement
XENGENdata scaling
RefineMethod to determine structure: PREVIOUS STRUCTURE
Starting model: PDB ENTRY 1HAH
Sigma F: 4
Displacement parametersB iso mean: 24 Å2
Least-squares processR factor R work: 0.155 / Highest resolution: 2.12 Å / Lowest resolution: 7 Å / Number reflection obs: 15585 / Percent reflection obs: 75
Refine hist #LASTHighest resolution: 2.12 Å / Lowest resolution: 7 Å
Number of atoms included #LASTProtein: 2298 / Nucleic acid: 0 / Ligand: 40 / Solvent: 165 / Total: 2503
Refine LS restraints
Refine IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONp_bond_d0.0200.020
X-RAY DIFFRACTIONp_angle_d0.0420.030
X-RAY DIFFRACTIONp_angle_deg
X-RAY DIFFRACTIONp_planar_d0.0490.045
X-RAY DIFFRACTIONp_hb_or_metal_coord
X-RAY DIFFRACTIONp_mcbond_it1.01.0
X-RAY DIFFRACTIONp_mcangle_it1.71.5
X-RAY DIFFRACTIONp_scbond_it2.42.0
X-RAY DIFFRACTIONp_scangle_it3.52.5
X-RAY DIFFRACTIONp_plane_restr0.0280.030
X-RAY DIFFRACTIONp_chiral_restr0.190.15
X-RAY DIFFRACTIONp_singtor_nbd0.220.60
X-RAY DIFFRACTIONp_multtor_nbd0.260.60
X-RAY DIFFRACTIONp_xhyhbond_nbd
X-RAY DIFFRACTIONp_xyhbond_nbd0.250.60
X-RAY DIFFRACTIONp_planar_tor4.3.
X-RAY DIFFRACTIONp_staggered_tor21.15.
X-RAY DIFFRACTIONp_orthonormal_tor
X-RAY DIFFRACTIONp_transverse_tor30.20.
X-RAY DIFFRACTIONp_special_tor
Software
*PLUS
Name: PROFFT / Classification: refinement
Least-squares process
*PLUS
R factor obs: 0.155

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