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- PDB-6eo8: Crystal structure of thrombin in complex with a novel glucose-con... -

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Basic information

Entry
Database: PDB / ID: 6eo8
TitleCrystal structure of thrombin in complex with a novel glucose-conjugated potent inhibitor
Components
  • (Prothrombin) x 2
  • Hirudin variant-2
KeywordsBLOOD CLOTTING / 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 / regulation of blood coagulation / neutrophil-mediated killing of gram-negative bacterium / 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 / 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 / antimicrobial humoral immune response mediated by antimicrobial peptide / 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 / 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 / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / cell surface receptor signaling pathway / blood microparticle / positive regulation of protein phosphorylation / G protein-coupled receptor signaling pathway / endoplasmic reticulum lumen / serine-type endopeptidase activity / signaling receptor binding / 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-2FN / Prothrombin / Hirudin variant-2
Similarity search - Component
Biological speciesHomo sapiens (human)
Hirudo medicinalis (medicinal leech)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.94 Å
AuthorsBelviso, B.D. / Caliandro, R. / Aresta, B.M. / De Candia, M. / Altomare, C.D.
CitationJournal: J. Med. Chem. / Year: 2014
Title: How a beta-D-glucoside side chain enhances binding affinity to thrombin of inhibitors bearing 2-chlorothiophene as P1 moiety: crystallography, fragment deconstruction study, and evaluation of ...Title: How a beta-D-glucoside side chain enhances binding affinity to thrombin of inhibitors bearing 2-chlorothiophene as P1 moiety: crystallography, fragment deconstruction study, and evaluation of antithrombotic properties.
Authors: Belviso, B.D. / Caliandro, R. / de Candia, M. / Zaetta, G. / Lopopolo, G. / Incampo, F. / Colucci, M. / Altomare, C.D.
History
DepositionOct 9, 2017Deposition site: PDBE / Processing site: PDBE
SupersessionDec 13, 2017ID: 4N3L
Revision 1.0Dec 13, 2017Provider: repository / Type: Initial release
Revision 1.1Mar 7, 2018Group: Source and taxonomy / Category: entity_src_gen
Item: _entity_src_gen.pdbx_host_org_ncbi_taxonomy_id / _entity_src_gen.pdbx_host_org_scientific_name
Revision 1.2Oct 16, 2019Group: Data collection / Category: reflns_shell

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
L: Prothrombin
H: Prothrombin
I: Hirudin variant-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,57610
Polymers35,4113
Non-polymers1,1657
Water1,44180
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4400 Å2
ΔGint-0 kcal/mol
Surface area12680 Å2
MethodPISA
Unit cell
Length a, b, c (Å)66.990, 71.660, 71.790
Angle α, β, γ (deg.)90.00, 99.70, 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 Prothrombin / Coagulation factor II


Mass: 4096.534 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: F2 / Production host: Homo sapiens (human) / References: UniProt: P00734, thrombin
#3: Protein/peptide Hirudin variant-2


Mass: 1534.554 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Hirudo medicinalis (medicinal leech) / Production host: Hirudo medicinalis (medicinal leech) / References: UniProt: P09945

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Protein , 1 types, 1 molecules H

#2: Protein Prothrombin / Coagulation factor II


Mass: 29780.219 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: F2 / Production host: Homo sapiens (human) / References: UniProt: P00734, thrombin

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Non-polymers , 3 types, 87 molecules

#4: Chemical
ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#5: Chemical ChemComp-2FN / N-(2-{[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methoxy}-6-[3-(beta-D-glucopyranosyloxy)propoxy]phenyl)-1-(propan-2-yl)piperidine-4-carboxamide


Mass: 696.208 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C32H42ClN3O10S / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 80 / Source method: isolated from a natural source / Formula: H2O

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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: 2.58 Å3/Da / Density % sol: 52.25 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 30% PEG 4000, 0.1M HEPES pH7.0, 0.75M NaCl, 0.04% NaN3, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 77 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU / Wavelength: 1.5418 Å
DetectorType: RIGAKU SATURN 944 / Detector: CCD / Date: Jul 23, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.94→70.76 Å / Num. obs: 24599 / % possible obs: 98.6 % / Redundancy: 3.3 % / Net I/σ(I): 1.7

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Processing

Software
NameVersionClassification
REFMAC5.8.0158refinement
MOSFLMdata reduction
SCALAdata scaling
Sir2014REMOphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.94→70.76 Å / Cor.coef. Fo:Fc: 0.948 / Cor.coef. Fo:Fc free: 0.92 / SU B: 5.55 / SU ML: 0.148 / Cross valid method: THROUGHOUT / ESU R: 0.177 / ESU R Free: 0.159 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.24757 1258 5.1 %RANDOM
Rwork0.20991 ---
obs0.21191 23372 98.92 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 33.265 Å2
Baniso -1Baniso -2Baniso -3
1--0.08 Å20 Å20.23 Å2
2---0.01 Å20 Å2
3---0.01 Å2
Refinement stepCycle: 1 / Resolution: 1.94→70.76 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2312 0 71 80 2463
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0180.022439
X-RAY DIFFRACTIONr_bond_other_d0.0030.022274
X-RAY DIFFRACTIONr_angle_refined_deg2.0361.9983289
X-RAY DIFFRACTIONr_angle_other_deg1.1423.0095273
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.8055278
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.99423.509114
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.20915425
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.1131520
X-RAY DIFFRACTIONr_chiral_restr0.1230.2345
X-RAY DIFFRACTIONr_gen_planes_refined0.010.0212610
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02505
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it2.8443.0351127
X-RAY DIFFRACTIONr_mcbond_other2.8113.0321126
X-RAY DIFFRACTIONr_mcangle_it4.1024.531400
X-RAY DIFFRACTIONr_mcangle_other4.1024.5341401
X-RAY DIFFRACTIONr_scbond_it3.3843.5491312
X-RAY DIFFRACTIONr_scbond_other3.3843.5491312
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other5.1785.1581889
X-RAY DIFFRACTIONr_long_range_B_refined7.08335.6442715
X-RAY DIFFRACTIONr_long_range_B_other7.08135.6652716
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.939→1.989 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.334 81 -
Rwork0.367 1573 -
obs--90.73 %

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