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- PDB-1ad8: COMPLEX OF THROMBIN WITH AND INHIBITOR CONTAINING A NOVEL P1 MOIETY -

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Basic information

Entry
Database: PDB / ID: 1ad8
TitleCOMPLEX OF THROMBIN WITH AND INHIBITOR CONTAINING A NOVEL P1 MOIETY
Components
  • HIRUDIN (53-65) PEPTIDE
  • THROMBIN (LARGE SUBUNIT)
  • THROMBIN (SMALL SUBUNIT)
KeywordsHYDROLASE/HYDROLASE INHIBITOR / COMPLEX (SERINE PROTEASE-INHIBITOR) / HYDROLASE / SERINE PROTEASE / COAGULANT / 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 / Serine proteases, trypsin domain profile. / Prothrombin/thrombin / Peptidase S1A, chymotrypsin family / Serine proteases, trypsin domain / Gla domain profile. / Proteinase inhibitor I14, hirudin / Gamma-carboxyglutamic acid-rich (GLA) domain / Kringle / Kringle domain profile. / Thrombin light chain domain superfamily / Kringle superfamily / Kringle domain / 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 / Removal of aminoterminal propeptides from gamma-carboxylated proteins / Trypsin / 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 / negative regulation of serine-type peptidase activity / 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-1
Function and homology information
Specimen sourceHirudo medicinalis (medicinal leech)
Homo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / 2 Å resolution
AuthorsSchreuder, H. / Tardif, C. / Malikayil, J.A.
CitationJournal: Biochemistry / Year: 1997
Title: Molecular design and characterization of an alpha-thrombin inhibitor containing a novel P1 moiety.
Authors: Malikayil, J.A. / Burkhart, J.P. / Schreuder, H.A. / Broersma Jr., R.J. / Tardif, C. / Kutcher 3rd., L.W. / Mehdi, S. / Schatzman, G.L. / Neises, B. / Peet, N.P.
Validation Report
SummaryFull reportAbout validation report
DateDeposition: Feb 24, 1997 / Release: Nov 12, 1997
RevisionDateData content typeGroupProviderType
1.0Nov 12, 1997Structure modelrepositoryInitial release
1.1Mar 3, 2008Structure modelVersion format compliance
1.2Jul 13, 2011Structure modelAtomic model / Database references / Derived calculations / Non-polymer description / Structure summary / Version format compliance

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
L: THROMBIN (SMALL SUBUNIT)
H: THROMBIN (LARGE SUBUNIT)
I: HIRUDIN (53-65) PEPTIDE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,8285
Polyers35,2403
Non-polymers5882
Water3,513195
1


TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
γ
α
β
Length a, b, c (Å)70.550, 72.050, 73.000
Angle α, β, γ (deg.)90.00, 101.00, 90.00
Int Tables number5
Space group name H-MC 1 2 1

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Components

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Protein/peptide , 3 types, 3 molecules LHI

#1: Protein/peptide THROMBIN (SMALL SUBUNIT)


Mass: 4096.534 Da / Num. of mol.: 1 / Source: (natural) Homo sapiens (human) / Genus: Homo / Tissue: BLOOD / References: UniProt: P00734, thrombin
#2: Protein/peptide THROMBIN (LARGE SUBUNIT)


Mass: 29780.219 Da / Num. of mol.: 1 / Source: (natural) Homo sapiens (human) / Genus: Homo / Tissue: BLOOD / References: UniProt: P00734, thrombin
#3: Protein/peptide HIRUDIN (53-65) PEPTIDE


Mass: 1363.399 Da / Num. of mol.: 1 / Source: (gene. exp.) Hirudo medicinalis (medicinal leech) / Genus: Hirudo / References: UniProt: P01050

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Non-polymers , 3 types, 197 molecules

#4: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Formula: Na / Sodium
#5: Chemical ChemComp-MDL / [DEHYDROXY-N-METHYL-TYROSYL-PROLINYL]-[4,4,5,5,5-PENTAFLUORO-3-OXY-1-[3-INDOLYL]-PENT-2-YL]AMINE


Mass: 564.547 Da / Num. of mol.: 1 / Formula: C28H29F5N4O3
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 195 / Formula: H2O / Water

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Details

Compound detailsTHROMBIN IS CLEAVED BETWEEN RESIDUES 15 AND 16. CHAIN IDENTIFIER *L* IS USED FOR RESIDUES 1C - 14K ...THROMBIN IS CLEAVED BETWEEN RESIDUES 15 AND 16. CHAIN IDENTIFIER *L* IS USED FOR RESIDUES 1C - 14K AND CHAIN IDENTIFIER *H* IS USED FOR RESIDUES 16 - 245. CHAIN IDENTIFIER *I* IS USED FOR HIRUDIN, RESIDUES 53 - 65.

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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: 2.5 / Density percent sol: 51 %
Crystal growMethod: vapor diffusion, hanging drop / pH: 7.3
Details: A DROP WITH 1.62 MG/ML PROTEIN, 0.375 M NACL, 0.09 M PHOSPHATE BUFFER (PH 7.3), 0.5 MM AZIDE, 4.9 MM INHIBITOR AND 15% (W/V) PEG8000 WAS EQUILIBRATED AGAINST 30% (W/V)PEG8000 IN 0.08 M PHOSPHATE BUFFER (PH 7.3), USING A HANGING DROP SETUP., vapor diffusion - hanging drop
Crystal grow
*PLUS
Method: vapor diffusion, hanging drop
components of the solutions
*PLUS
IDConcCommon nameCrystal IDSol IDChemical formula
11.62 mg/mlprotein1drop
20.375 M1dropNaCl
30.09 Mphosphate1drop
40.5 mM1dropNaN3
54.9 mMpeptide II1drop
615 %(w/v)PEG80001drop
730 %(w/v)PEG80001reservoir
80.08 Mphosphate1reservoir
90.5 mM1reservoirNaN3

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Data collection

DiffractionMean temperature: 277 kelvins
SourceSource: ROTATING ANODE / Type: SIEMENS / Wavelength: 1.5418
DetectorType: RIGAKU / Detector: IMAGE PLATE / Collection date: Jul 11, 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 Å / D resolution low: 1 Å / Number obs: 23326 / Observed criterion sigma I: 0 / Rsym value: 0.049 / NetI over sigmaI: 22 / Redundancy: 2.65 % / Percent possible obs: 95.8
Reflection shellHighest resolution: 2 Å / Lowest resolution: 2.1 Å / MeanI over sigI obs: 3.7 / Rsym value: 0.315 / Redundancy: 2.2 % / Percent possible all: 94.5
Reflection
*PLUS
Number measured all: 61748 / Rmerge I obs: 0.049

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Processing

Software
NameVersionClassification
XDSdata scaling
XSCALEdata scaling
X-PLOR3.1model building
X-PLOR3.1refinement
XDSdata reduction
X-PLOR3.1phasing
RefineMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: THROMBIN-HIRUGEN-PEPTIDE 1A COMPLEX (UNPUBLISHED)

Data cutoff high absF: 1 / Data cutoff low absF: 0.1 / Isotropic thermal model: RESTRAINED / Sigma F: 0
Displacement parametersB iso mean: 37.1 Å2
Least-squares processR factor R work: 0.205 / R factor obs: 0.205 / Highest resolution: 2 Å / Lowest resolution: 8 Å / Number reflection obs: 20795 / Percent reflection obs: 86.8
Refine analyzeLuzzati d res low obs: 8 Å
Refine hist #LASTHighest resolution: 2 Å / Lowest resolution: 8 Å
Number of atoms included #LASTProtein: 2344 / Nucleic acid: 0 / Ligand: 41 / Solvent: 195 / Total: 2580
Refine LS restraints
Refine IDTypeDev ideal
X-RAY DIFFRACTIONx_bond_d0.012
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_deg1.8
X-RAY DIFFRACTIONx_angle_deg_na
X-RAY DIFFRACTIONx_angle_deg_prot
X-RAY DIFFRACTIONx_dihedral_angle_d25.4
X-RAY DIFFRACTIONx_dihedral_angle_d_na
X-RAY DIFFRACTIONx_dihedral_angle_d_prot
X-RAY DIFFRACTIONx_improper_angle_d1.43
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
Refine LS shellHighest resolution: 2 Å / R factor R work: 0.334 / Lowest resolution: 2.09 Å / Number reflection R work: 2322 / Total number of bins used: 8 / Percent reflection obs: 77.2
Xplor file
Refine IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PARHCSDX.PROTOPHCSDX.PRO
X-RAY DIFFRACTION2INHIBITOR.PAR103752.TOP
X-RAY DIFFRACTION3WAT.PARWAT.TOP
Software
*PLUS
Name: X-PLOR / Version: 3.1 / Classification: refinement
Refine LS restraints
*PLUS
Refine IDTypeDev ideal
X-RAY DIFFRACTIONx_dihedral_angle_d
X-RAY DIFFRACTIONx_dihedral_angle_deg25.4
X-RAY DIFFRACTIONx_improper_angle_d
X-RAY DIFFRACTIONx_improper_angle_deg1.43

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