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- PDB-1tq7: Crystal structure of the anticoagulant thrombin mutant W215A/E217... -

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Basic information

Entry
Database: PDB / ID: 1tq7
TitleCrystal structure of the anticoagulant thrombin mutant W215A/E217A bound to PPACK
Components(Prothrombin) x 2
KeywordsHYDROLASE/HYDROLASE INHIBITOR / thrombin / anticoagulant / BLOOD CLOTTING / PPACK / 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 / 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
Epsilon-Thrombin; Chain L / Thrombin light chain domain / Prothrombin/thrombin / Thrombin light chain / Thrombin light chain domain superfamily / Thrombin light chain / Kringle domain / Kringle / Kringle, conserved site / Kringle superfamily ...Epsilon-Thrombin; Chain L / Thrombin light chain domain / 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 / Few Secondary Structures / Irregular / 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
D-Phe-Pro-Arg-CH2Cl / Chem-0G6 / Prothrombin
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.4 Å
AuthorsPineda, A.O. / Chen, Z.-W. / Caccia, S. / Savvides, S.N. / Waksman, G. / Mathews, F.S. / Di Cera, E.
CitationJournal: J.Biol.Chem. / Year: 2004
Title: The anticoagulant thrombin mutant W215A/E217A has a collapsed primary specificity pocket
Authors: Pineda, A.O. / Chen, Z.-W. / Caccia, S. / Cantwell, A.M. / Savvides, S.N. / Waksman, G. / Mathews, F.S. / Di Cera, E.
History
DepositionJun 16, 2004Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 3, 2004Provider: repository / Type: Initial release
Revision 1.1Apr 30, 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
Revision 1.3Feb 27, 2013Group: Other
Revision 1.4Jul 29, 2020Group: Data collection / Derived calculations / Structure summary
Category: chem_comp / entity ...chem_comp / entity / pdbx_chem_comp_identifier / pdbx_entity_nonpoly / struct_conn / struct_site / struct_site_gen
Item: _chem_comp.name / _chem_comp.type ..._chem_comp.name / _chem_comp.type / _entity.pdbx_description / _pdbx_entity_nonpoly.name / _struct_conn.conn_type_id / _struct_conn.id / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.pdbx_ptnr1_PDB_ins_code / _struct_conn.pdbx_role / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 1.5Oct 27, 2021Group: Database references / Structure summary / Category: chem_comp / database_2 / struct_ref_seq_dif
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI ..._chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details
Revision 1.6Aug 23, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.7Mar 13, 2024Group: Source and taxonomy / Structure summary / Category: entity / pdbx_entity_src_syn / Item: _entity.details

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Prothrombin
B: Prothrombin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,4447
Polymers34,5732
Non-polymers8715
Water2,612145
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4790 Å2
ΔGint-103 kcal/mol
Surface area13400 Å2
MethodPISA
Unit cell
Length a, b, c (Å)51.110, 73.830, 87.330
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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Protein/peptide / Protein / Sugars , 3 types, 3 molecules AB

#1: Protein/peptide Prothrombin / Coagulation factor II


Mass: 5151.698 Da / Num. of mol.: 1 / Fragment: light chain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: F2 / Plasmid: HPC4-pNUT / Cell (production host): kidney / Production host: Cricetulus griseus (Chinese hamster) / References: UniProt: P00734, thrombin
#2: Protein Prothrombin / Coagulation factor II


Mass: 29420.891 Da / Num. of mol.: 1 / Fragment: heavy chain / Mutation: W215A/E217A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: F2 / Plasmid: HPC4-pNUT / Cell (production host): kidney / Production host: Cricetulus griseus (Chinese hamster) / 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: isolated from a genetically manipulated source
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 , 3 types, 149 molecules

#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Zn / Details: PPACK inhibitor
#4: Chemical ChemComp-0G6 / D-phenylalanyl-N-[(2S,3S)-6-{[amino(iminio)methyl]amino}-1-chloro-2-hydroxyhexan-3-yl]-L-prolinamide / PPACK


Type: peptide-like, Peptide-like / Class: Inhibitor / Mass: 453.986 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H34ClN6O3 / References: D-Phe-Pro-Arg-CH2Cl
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 145 / Source method: isolated from a natural source / Formula: H2O

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Details

Nonpolymer detailsTHE INHIBITOR IS COVALENTLY CONNECTED TO ACTIVE_SITE RESIDUES: 1) VIA A HEMIKETAL GROUP TO OG SER B ...THE INHIBITOR IS COVALENTLY CONNECTED TO ACTIVE_SITE RESIDUES: 1) VIA A HEMIKETAL GROUP TO OG SER B 195, 2) VIA A METHYLENE GROUP TO NE2 HIS B 57.

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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: 2.35 Å3/Da / Density % sol: 47.73 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 18% PEG 8000, 0.2 M zinc acetate, 0.1 M sodium cacodylate, pH 6.5, VAPOR DIFFUSION, HANGING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 148 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS II / Detector: IMAGE PLATE / Date: Jun 2, 2002 / Details: mirror
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.4→30 Å / Num. all: 13490 / Num. obs: 13234 / % possible obs: 98.1 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Biso Wilson estimate: 34.9 Å2
Reflection shellResolution: 2.4→2.49 Å / % possible all: 90.6

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Processing

Software
NameVersionClassification
CNS1refinement
DENZOdata reduction
SCALEPACKdata scaling
CNSphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1PPB

1ppb


Resolution: 2.4→28.31 Å / Rfactor Rfree error: 0.007 / Data cutoff high absF: 756394.32 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.243 1299 10.3 %RANDOM
Rwork0.205 ---
all0.205 13463 --
obs0.205 12594 93.5 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 28.6212 Å2 / ksol: 0.328975 e/Å3
Displacement parametersBiso mean: 31.7 Å2
Baniso -1Baniso -2Baniso -3
1-0.8 Å20 Å20 Å2
2---8.63 Å20 Å2
3---7.83 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.37 Å0.29 Å
Luzzati d res low-5 Å
Luzzati sigma a0.41 Å0.27 Å
Refinement stepCycle: LAST / Resolution: 2.4→28.31 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2379 0 47 145 2571
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.008
X-RAY DIFFRACTIONc_angle_deg1.5
X-RAY DIFFRACTIONc_dihedral_angle_d26.6
X-RAY DIFFRACTIONc_improper_angle_d1.68
X-RAY DIFFRACTIONc_mcbond_it2.571.5
X-RAY DIFFRACTIONc_mcangle_it4.112
X-RAY DIFFRACTIONc_scbond_it1.972
X-RAY DIFFRACTIONc_scangle_it3.012.5
LS refinement shellResolution: 2.4→2.55 Å / Rfactor Rfree error: 0.025 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.344 195 9.9 %
Rwork0.273 1767 -
obs-1199 88.8 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PROTEIN_REP-DAMINO.PARAMPROTEIN-DAMINO.TOP
X-RAY DIFFRACTION2NAG.PARAMNAG.TOPO
X-RAY DIFFRACTION3WATER_REP.PARAMWATER.TOP
X-RAY DIFFRACTION4ION.PARAMION.TOP
X-RAY DIFFRACTION5CH2.PARAMCH2.TOPO

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