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- PDB-6zv8: Crystal Structure of Thrombin in complex with compound51 -

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Basic information

Entry
Database: PDB / ID: 6zv8
TitleCrystal Structure of Thrombin in complex with compound51
Components
  • (Prothrombin) x 2
  • Hirudin-2
KeywordsBLOOD CLOTTING / COAGULATION / CONVERTION OF FIBRINOGEN TO FIBRIN / BLOOD CLOTTING INHIBITOR / THROMBIN INHIBITOR / HYDROLASE
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 / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan
Similarity search - Domain/homology
Chem-QQT / Prothrombin / Hirudin-2
Similarity search - Component
Biological speciesHomo sapiens (human)
Hirudo medicinalis (medicinal leech)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.7 Å
AuthorsSchafer, M.
CitationJournal: J.Med.Chem. / Year: 2020
Title: Design, Synthesis, and Pharmacological Characterization of a Neutral, Non-Prodrug Thrombin Inhibitor with Good Oral Pharmacokinetics.
Authors: Hillisch, A. / Gericke, K.M. / Allerheiligen, S. / Roehrig, S. / Schaefer, M. / Tersteegen, A. / Schulz, S. / Lienau, P. / Gnoth, M. / Puetter, V. / Hillig, R.C. / Heitmeier, S.
History
DepositionJul 24, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 26, 2020Provider: repository / Type: Initial release
Revision 1.1Nov 11, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_abbrev / _citation.pdbx_database_id_DOI ..._citation.journal_abbrev / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Nov 25, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.3May 1, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,0105
Polymers35,2973
Non-polymers7132
Water4,648258
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3300 Å2
ΔGint-12 kcal/mol
Surface area12810 Å2
MethodPISA
Unit cell
Length a, b, c (Å)69.166, 70.342, 71.372
Angle α, β, γ (deg.)90.000, 100.280, 90.000
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 / Fragment: POTENIALLY THE FIRST EXON / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P00734, thrombin
#3: Protein/peptide Hirudin-2 / Hirudin II


Mass: 1420.451 Da / Num. of mol.: 1 / Fragment: HIRUDIN FRAGMENT / Source method: obtained synthetically / Source: (synth.) Hirudo medicinalis (medicinal leech) / References: UniProt: P28504

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Protein / Sugars , 2 types, 2 molecules H

#2: Protein Prothrombin / Coagulation factor II


Mass: 29780.219 Da / Num. of mol.: 1 / Fragment: THE MAJORITY OF THE SEQUENCE / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P00734, thrombin
#5: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Non-polymers , 2 types, 259 molecules

#4: Chemical ChemComp-QQT / [2-[[(1~{S})-1-(3-chlorophenyl)-2-fluoranyl-ethyl]amino]-7-methoxy-1,3-benzoxazol-5-yl]-[(2~{S},5~{S})-5-(2-hydroxyethyl)-2-methyl-morpholin-4-yl]methanone


Mass: 491.940 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H27ClFN3O5 / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 258 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY

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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: 2.42 Å3/Da / Density % sol: 49.17 %
Crystal growTemperature: 283 K / Method: vapor diffusion, hanging drop
Details: 0.02 M phosphate buffer pH 7.5, 27% PEG 8000, 100 mM NaCl

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: BRUKER AXS MICROSTAR / Wavelength: 1.54187 Å
DetectorType: Nonius Kappa CCD / Detector: CCD / Date: Nov 9, 2012 / Details: MIRRORS
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54187 Å / Relative weight: 1
ReflectionResolution: 1.59→70.23 Å / Num. obs: 130734 / % possible obs: 89.2 % / Observed criterion σ(I): 2 / Redundancy: 2.84 % / Rmerge(I) obs: 0.06 / Net I/σ(I): 12.95 / Num. measured all: 130734
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. possibleNum. unique obsNet I/σ(I) obs% possible all
1.59-1.611.960.2798197292.3989
1.61-1.642.080.275239421512.589.8
1.64-1.682.220.264293926563.0690.4
1.68-1.722.330.247265224223.4991.3
1.72-1.762.40.202242322304.4892
1.76-1.812.470.176273225405.3193
1.81-1.862.570.159246623096.1393.6
1.86-1.912.620.142220120726.9694.1
1.91-1.972.70.118236822248.4593.9
1.97-2.042.770.1032387220510.2392.4
2.04-2.122.920.0972369219411.7892.6
2.12-2.213.050.0982286209112.7991.5
2.21-2.323.210.0972314207814.1389.8
2.32-2.463.350.092419216516.2789.5
2.46-2.653.340.0742468214519.2186.9
2.65-2.913.170.0592442202022.8882.7
2.91-3.333.240.0532501203327.1481.3
3.33-4.23.310.0452514204533.1181.3
4.2-70.233.850.0452550203838.1579.9

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
SAINTdata reduction
XPREP2008/2data scaling
PHASERphasing
REFMACREFMAC 5.7.0029refinement
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: INHOUSE

Resolution: 1.7→70.22 Å / Cor.coef. Fo:Fc: 0.936 / Cor.coef. Fo:Fc free: 0.903 / SU B: 2.281 / SU ML: 0.078 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.13 / ESU R Free: 0.129 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.2473 1618 4.9 %RANDOM
Rwork0.203 ---
obs0.2052 31333 88.88 %-
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 max: 73.75 Å2 / Biso mean: 18.885 Å2 / Biso min: 5.88 Å2
Baniso -1Baniso -2Baniso -3
1-0.57 Å2-0 Å2-0.38 Å2
2---0.45 Å20 Å2
3----0.05 Å2
Refinement stepCycle: final / Resolution: 1.7→70.22 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2342 0 14 258 2614
Biso mean--48.81 27.75 -
Num. residues----289
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONBOND LENGTHS REFINED (A)0.0230.022418
X-RAY DIFFRACTIONBOND LENGTHS OTHERS (A)0.0020.022313
X-RAY DIFFRACTIONBOND ANGLES REFINED (DEGREES)2.2121.9993209
X-RAY DIFFRACTIONBOND ANGLES OTHERS (DEGREES)0.9153.0055258
X-RAY DIFFRACTIONTORSION ANGLES, PERIOD 1 (DEGREES)6.865248
X-RAY DIFFRACTIONTORSION ANGLES, PERIOD 2 (DEGREES)33.05923.596114
X-RAY DIFFRACTIONTORSION ANGLES, PERIOD 3 (DEGREES)14.35315426
X-RAY DIFFRACTIONTORSION ANGLES, PERIOD 4 (DEGREES)12.9481519
X-RAY DIFFRACTIONCHIRAL-CENTER RESTRAINTS (A**3)0.1210.2344
X-RAY DIFFRACTIONGENERAL PLANES REFINED (A)0.0120.0212452
X-RAY DIFFRACTIONGENERAL PLANES OTHERS (A)0.0010.02519
X-RAY DIFFRACTIONNON-BONDED CONTACTS REFINED (A)
X-RAY DIFFRACTIONNON-BONDED CONTACTS OTHERS (A)
X-RAY DIFFRACTIONNON-BONDED TORSION REFINED (A)
X-RAY DIFFRACTIONNON-BONDED TORSION OTHERS (A)
X-RAY DIFFRACTIONH-BOND (X...Y) REFINED (A)
X-RAY DIFFRACTIONSYMMETRY VDW REFINED (A)
X-RAY DIFFRACTIONSYMMETRY VDW OTHERS (A)
X-RAY DIFFRACTIONSYMMETRY H-BOND REFINED (A)
LS refinement shellResolution: 1.7→1.744 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection
Rfree0.307 122
Rwork0.209 2336
all-2458

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