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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 / homology
Function and homology information


negative regulation of serine-type peptidase activity / 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 / Defective factor XII causes hereditary angioedema / thrombin / neutrophil-mediated killing of gram-negative bacterium / regulation of blood coagulation / ligand-gated ion channel signaling pathway ...negative regulation of serine-type peptidase activity / 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 / Defective factor XII causes hereditary angioedema / thrombin / neutrophil-mediated killing of gram-negative bacterium / regulation of blood coagulation / ligand-gated ion channel signaling pathway / Defective F8 cleavage by thrombin / Platelet Aggregation (Plug Formation) / negative regulation of platelet activation / negative regulation of astrocyte differentiation / 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 / regulation of cytosolic calcium ion concentration / fibrinolysis / Intrinsic Pathway of Fibrin Clot Formation / Peptide ligand-binding receptors / positive regulation of release of sequestered calcium ion into cytosol / Regulation of Complement cascade / acute-phase response / lipopolysaccharide binding / Cell surface interactions at the vascular wall / negative regulation of proteolysis / positive regulation of receptor signaling pathway via JAK-STAT / growth factor activity / serine-type endopeptidase inhibitor activity / positive regulation of insulin secretion / response to wounding / platelet activation / Golgi lumen / positive regulation of protein localization to nucleus / 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 / G alpha (q) signalling events / positive regulation of cell growth / collagen-containing extracellular matrix / blood microparticle / cell surface receptor signaling pathway / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / G protein-coupled receptor signaling pathway / positive regulation of protein phosphorylation / endoplasmic reticulum lumen / signaling receptor binding / serine-type endopeptidase activity / calcium ion binding / positive regulation of cell population proliferation / proteolysis / extracellular space / extracellular exosome / extracellular region / plasma membrane
Similarity search - Function
Thrombin inhibitor hirudin / Hirudin / Proteinase inhibitor I14, hirudin / Hirudin/antistatin / Prothrombin/thrombin / Thrombin light chain / Thrombin light chain domain superfamily / Thrombin light chain / Kringle domain / Kringle ...Thrombin inhibitor hirudin / Hirudin / Proteinase inhibitor I14, 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 domain profile. / Trypsin-like serine protease / Serine proteases, trypsin family, serine active site. / 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-MDL / Prothrombin / Hirudin variant-1
Similarity search - Component
Biological speciesHirudo medicinalis (medicinal leech)
Homo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2 Å
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.
History
DepositionFeb 24, 1997Processing site: BNL
Revision 1.0Nov 12, 1997Provider: repository / Type: Initial release
Revision 1.1Mar 3, 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

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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
Polymers35,2403
Non-polymers5882
Water3,513195
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
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-MC121

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Components

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Protein/peptide , 2 types, 2 molecules LI

#1: Protein/peptide THROMBIN (SMALL SUBUNIT)


Mass: 4096.534 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / Tissue: BLOOD / References: UniProt: P00734, thrombin
#3: Protein/peptide HIRUDIN (53-65) PEPTIDE


Mass: 1363.399 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Hirudo medicinalis (medicinal leech) / References: UniProt: P01050

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Protein , 1 types, 1 molecules H

#2: Protein THROMBIN (LARGE SUBUNIT)


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

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Non-polymers , 3 types, 197 molecules

#4: Chemical ChemComp-NA / SODIUM ION


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


Type: peptide-like / Mass: 564.547 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H29F5N4O3
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 195 / 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 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 Å3/Da / Density % 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 ...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
IDConc.Common 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 K
Diffraction sourceSource: ROTATING ANODE / Type: SIEMENS / Wavelength: 1.5418
DetectorType: RIGAKU / Detector: IMAGE PLATE / Date: Jul 11, 1995
RadiationMonochromator: GRAPHITE(002) / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2→1000 Å / Num. obs: 23326 / % possible obs: 95.8 % / Observed criterion σ(I): 0 / Redundancy: 2.65 % / Rsym value: 0.049 / Net I/σ(I): 22
Reflection shellResolution: 2→2.1 Å / Redundancy: 2.2 % / Mean I/σ(I) obs: 3.7 / Rsym value: 0.315 / % possible all: 94.5
Reflection
*PLUS
Num. 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
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: THROMBIN-HIRUGEN-PEPTIDE 1A COMPLEX (UNPUBLISHED)

Resolution: 2→8 Å / Data cutoff high absF: 10000000 / Data cutoff low absF: 0.1 / Isotropic thermal model: RESTRAINED / σ(F): 0
RfactorNum. reflection% reflection
Rwork0.205 --
obs0.205 20795 86.8 %
Displacement parametersBiso mean: 37.1 Å2
Refine analyzeLuzzati d res low obs: 8 Å
Refinement stepCycle: LAST / Resolution: 2→8 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2344 0 41 195 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
LS refinement shellResolution: 2→2.09 Å / Total num. of bins used: 8
RfactorNum. reflection% reflection
Rwork0.334 2322 -
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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