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- PDB-1wbg: Active site thrombin inhibitors -

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Basic information

Entry
Database: PDB / ID: 1wbg
TitleActive site thrombin inhibitors
Components
  • HIRUGEN
  • THROMBIN HEAVY CHAIN
  • THROMBIN LIGHT CHAIN
KeywordsHYDROLASE/HYDROLASE INHIBITOR / BLOOD COAGULATION-INHIBITOR / SERINE PROTEASE / BLOOD COAGULATION / ACUTE PHASE / CALCIUM-BINDING / DISEASE MUTATION / GAMMA-CARBOXYGLUTAMIC ACID / GLYCOPROTEIN / KRINGLE / POLYMORPHISME / VITAMIN K / ZYMOGEN / SULFATION / 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 / 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 ...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 / 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 / Regulation of Complement cascade / acute-phase response / Cell surface interactions at the vascular wall / lipopolysaccharide binding / 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 / platelet activation / response to wounding / 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 / positive regulation of cell growth / G alpha (q) signalling events / collagen-containing extracellular matrix / blood microparticle / cell surface receptor signaling pathway / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of protein phosphorylation / G protein-coupled receptor signaling pathway / 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. / Serine proteases, trypsin family, serine active site. / 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-L03 / Prothrombin / Hirudin variant-2
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
HIRUDO MEDICINALIS (medicinal leech)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsHartshorn, M.J. / Murray, C.W. / Cleasby, A. / Frederickson, M. / Tickle, I.J. / Jhoti, H.
CitationJournal: J.Med.Chem. / Year: 2005
Title: Fragment-Based Lead Discovery Using X-Ray Crystallography
Authors: Hartshorn, M.J. / Murray, C.W. / Cleasby, A. / Frederickson, M. / Tickle, I.J. / Jhoti, H.
History
DepositionNov 1, 2004Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 27, 2005Provider: 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 1.2Jun 28, 2017Group: Data collection / Category: diffrn_source / Item: _diffrn_source.type
Revision 1.3Dec 13, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_conn / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_leaving_atom_flag / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Remark 700 SHEET DETERMINATION METHOD: DSSP THE SHEETS PRESENTED AS "BB" IN EACH CHAIN ON SHEET RECORDS BELOW ... SHEET DETERMINATION METHOD: DSSP THE SHEETS PRESENTED AS "BB" IN EACH CHAIN ON SHEET RECORDS BELOW IS ACTUALLY AN 6-STRANDED BARREL THIS IS REPRESENTED BY A 7-STRANDED SHEET IN WHICH THE FIRST AND LAST STRANDS ARE IDENTICAL.

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: THROMBIN LIGHT CHAIN
B: THROMBIN HEAVY CHAIN
I: HIRUGEN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,7007
Polymers35,2403
Non-polymers4604
Water6,990388
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
Unit cell
Length a, b, c (Å)69.392, 71.785, 71.733
Angle α, β, γ (deg.)90.00, 99.87, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11B-2144-

HOH

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Components

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Protein/peptide , 2 types, 2 molecules AI

#1: Protein/peptide THROMBIN LIGHT CHAIN / / THROMBIN / COAGULATION FACTOR II


Mass: 4096.534 Da / Num. of mol.: 1 / Fragment: 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
#3: Protein/peptide HIRUGEN


Mass: 1363.399 Da / Num. of mol.: 1 / Fragment: PEPTIDE FRAGMENT OF HIRUGEN, RESIDUES 62-71 / Source method: obtained synthetically / Source: (synth.) HIRUDO MEDICINALIS (medicinal leech) / References: UniProt: P09945

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Protein , 1 types, 1 molecules B

#2: Protein THROMBIN HEAVY CHAIN / / THROMBIN / COAGULATION FACTOR II


Mass: 29780.219 Da / Num. of mol.: 1 / Fragment: 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

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Non-polymers , 3 types, 392 molecules

#4: Chemical ChemComp-L03 / 3-(4-CHLOROPHENYL)-5-(METHYLTHIO)-4H-1,2,4-TRIAZOLE


Mass: 225.698 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C9H8ClN3S
#5: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE / Dimethyl sulfoxide


Mass: 78.133 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 388 / Source method: isolated from a natural source / Formula: H2O

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Details

Compound detailsFUNCTION: THROMBIN, WHICH CLEAVES BONDS AFTER ARG AND LYS, CONVERTS FIBRINOGEN TO FIBRIN AND ...FUNCTION: THROMBIN, WHICH CLEAVES BONDS AFTER ARG AND LYS, CONVERTS FIBRINOGEN TO FIBRIN AND ACTIVATES FACTORS V, VII, VIII, XIII, AND, IN COMPLEX WITH THROMBOMODULIN, PROTEIN C. CATALYTIC ACTIVITY: PREFERENTIAL CLEAVAGE: ARG-|-GLY; ACTIVATES FIBRINOGEN TO FIBRIN AND RELEASES FIBRINOPEPTIDE A AND B. SUBCELLULAR LOCATION: EXTRACELLULAR. TISSUE SPECIFICITY: EXPRESSED BY THE LIVER AND SECRETED IN PLASMA. DISEASE: DEFECTS IN F2 ARE THE CAUSE OF VARIOUS FORMS OF DYSPROTHROMBINEMIA [MIM:176930]. SIMILARITY: BELONGS TO THE PEPTIDASE S1 FAMILY. SIMILARITY: CONTAINS 1 GAMMA-CARBOXY-GLUTAMATE DOMAIN (GLA) DOMAIN. SIMILARITY: CONTAINS 2 KRINGLE DOMAINS. FUNCTION: HIRUDIN IS A POTENT THROMBIN-SPECIFIC PROTEASE INHIBITOR. IT FORMS A STABLE NON-COVALENT COMPLEX WITH ALPHA- THROMBIN, THEREBY ABOLISHING ITS ABILITY TO CLEAVE FIBRINOGEN. SUBCELLULAR LOCATION: SECRETED.

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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: 50.75 %
Crystal growpH: 7.5 / Details: PH 7.50

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RUH3R / Wavelength: 1.54
DetectorType: RIGAKU CCD / Detector: CCD / Date: Dec 4, 2002 / Details: CONFOCAL MULTILAYER
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 2.2→27 Å / Num. obs: 17712 / % possible obs: 97.6 % / Redundancy: 2.04 % / Rmerge(I) obs: 0.07 / Net I/σ(I): 10.1
Reflection shellResolution: 2.2→2.28 Å / Redundancy: 1.85 % / Rmerge(I) obs: 0.23 / Mean I/σ(I) obs: 3.6 / % possible all: 95.4

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Processing

Software
NameVersionClassification
REFMAC5.2.0005refinement
d*TREKdata reduction
d*TREKdata scaling
IN-HOUSESOFTWAREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1QJ1

1qj1


Resolution: 2.2→27.21 Å / Cor.coef. Fo:Fc: 0.957 / Cor.coef. Fo:Fc free: 0.895 / SU B: 5.98 / SU ML: 0.154 / Cross valid method: THROUGHOUT / ESU R: 0.272 / ESU R Free: 0.247 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. DISORDER AT TWO-FOLD; ARG B 75 CLASHES. THE OCCUPANCY OF SIDE CHAIN ATOMS WAS SET TO 0 FOR REFINEMENT. THESE ATOMS REMOVED FOR DURING PDB ANNOTATION.
RfactorNum. reflection% reflectionSelection details
Rfree0.265 876 5.1 %RANDOM
Rwork0.166 ---
obs0.171 16409 97.6 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 22.71 Å2
Baniso -1Baniso -2Baniso -3
1-1.22 Å20 Å2-0.38 Å2
2---1.47 Å20 Å2
3---0.11 Å2
Refinement stepCycle: LAST / Resolution: 2.2→27.21 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2369 0 26 388 2783
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0222452
X-RAY DIFFRACTIONr_bond_other_d0.0040.022193
X-RAY DIFFRACTIONr_angle_refined_deg1.431.9663308
X-RAY DIFFRACTIONr_angle_other_deg0.80835109
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.8635287
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.61623.729118
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.83115431
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.1861519
X-RAY DIFFRACTIONr_chiral_restr0.0890.2337
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.022682
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02500
X-RAY DIFFRACTIONr_nbd_refined0.2130.2501
X-RAY DIFFRACTIONr_nbd_other0.1870.22343
X-RAY DIFFRACTIONr_nbtor_refined0.180.21160
X-RAY DIFFRACTIONr_nbtor_other0.0850.21352
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1440.2108
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.150.27
X-RAY DIFFRACTIONr_symmetry_vdw_other0.2750.251
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1040.28
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it3.251880
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it3.71962339
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it3.49561210
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it4.4987.5969
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.2→2.26 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rfree0.356 65
Rwork0.186 1169

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