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- PDB-2pgq: Human thrombin mutant C191A-C220A in complex with the inhibitor PPACK -

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Basic information

Entry
Database: PDB / ID: 2pgq
TitleHuman thrombin mutant C191A-C220A in complex with the inhibitor PPACK
Components
  • Thrombin heavy chain
  • Thrombin light chain
KeywordsHYDROLASE/HYDROLASE INHIBITOR / serine protease / HYDROLASE-HYDROLASE INHIBITOR COMPLEX
Function / homology
Function and homology information


cytolysis by host of symbiont cells / thrombospondin receptor activity / Defective factor XII causes hereditary angioedema / thrombin / thrombin-activated receptor signaling pathway / negative regulation of astrocyte differentiation / regulation of blood coagulation / positive regulation of phospholipase C-activating G protein-coupled receptor signaling pathway / neutrophil-mediated killing of gram-negative bacterium / Defective F8 cleavage by thrombin ...cytolysis by host of symbiont cells / thrombospondin receptor activity / Defective factor XII causes hereditary angioedema / thrombin / thrombin-activated receptor signaling pathway / negative regulation of astrocyte differentiation / regulation of blood coagulation / positive regulation of phospholipase C-activating G protein-coupled receptor signaling pathway / neutrophil-mediated killing of gram-negative bacterium / Defective F8 cleavage by thrombin / Platelet Aggregation (Plug Formation) / ligand-gated ion channel signaling pathway / positive regulation of collagen biosynthetic process / negative regulation of platelet activation / negative regulation of blood coagulation / positive regulation of blood coagulation / negative regulation of fibrinolysis / regulation of cytosolic calcium ion concentration / Transport of gamma-carboxylated protein precursors from the endoplasmic reticulum to the Golgi apparatus / Gamma-carboxylation of protein precursors / Common Pathway of Fibrin Clot Formation / Removal of aminoterminal propeptides from gamma-carboxylated proteins / fibrinolysis / Intrinsic Pathway of Fibrin Clot Formation / negative regulation of proteolysis / negative regulation of cytokine production involved in inflammatory response / Peptide ligand-binding receptors / Regulation of Complement cascade / positive regulation of release of sequestered calcium ion into cytosol / acute-phase response / Cell surface interactions at the vascular wall / positive regulation of receptor signaling pathway via JAK-STAT / growth factor activity / lipopolysaccharide binding / positive regulation of insulin secretion / platelet activation / response to wounding / positive regulation of protein localization to nucleus / Golgi lumen / 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 / regulation of cell shape / heparin binding / Thrombin signalling through proteinase activated receptors (PARs) / : / positive regulation of cell growth / blood microparticle / G alpha (q) signalling events / cell surface receptor signaling pathway / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor ligand activity / endoplasmic reticulum lumen / signaling receptor binding / serine-type endopeptidase activity / positive regulation of cell population proliferation / calcium ion binding / 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 ...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 / Serine proteases, trypsin family, histidine active site. / Peptidase S1A, chymotrypsin family / Serine proteases, trypsin family, serine active site. / Serine proteases, trypsin domain profile. / 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 / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsBush-Pelc, L.A. / Marino, F. / Chen, Z. / Pineda, A.O. / Mathews, F.S. / Di Cera, E.
Citation
Journal: J.Biol.Chem. / Year: 2007
Title: Important role of the cys-191 cys-220 disulfide bond in thrombin function and allostery
Authors: Bush-Pelc, L.A. / Marino, F. / Chen, Z. / Pineda, A.O. / Mathews, F.S. / Di Cera, E.
#1: Journal: J.Biol.Chem. / Year: 2004
Title: Molecular dissection of Na+ binding to thrombin
Authors: Pineda, A.O. / Carrell, C.J. / Bush, L.A. / Prasad, S. / Caccia, S. / Chen, Z.W. / Mathews, F.S. / Di Cera, E.
History
DepositionApr 10, 2007Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 17, 2007Provider: repository / Type: Initial release
Revision 1.1Apr 21, 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 1.4Sep 25, 2013Group: Derived calculations
Revision 1.5Jul 29, 2020Group: Data collection / Derived calculations / Structure summary
Category: chem_comp / entity ...chem_comp / entity / pdbx_chem_comp_identifier / pdbx_entity_nonpoly / pdbx_struct_conn_angle / struct_conn / struct_conn_type / 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 / _pdbx_struct_conn_angle.ptnr1_PDB_ins_code / _pdbx_struct_conn_angle.ptnr1_auth_asym_id / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr1_symmetry / _pdbx_struct_conn_angle.ptnr3_PDB_ins_code / _pdbx_struct_conn_angle.ptnr3_auth_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.ptnr3_symmetry / _pdbx_struct_conn_angle.value / _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_ptnr2_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 / _struct_conn.ptnr2_symmetry / _struct_conn_type.id
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 1.6Oct 20, 2021Group: Database references / Source and taxonomy / Structure summary
Category: chem_comp / database_2 ...chem_comp / database_2 / entity / pdbx_entity_src_syn / 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 / _entity.pdbx_description / _entity.pdbx_fragment / _pdbx_entity_src_syn.ncbi_taxonomy_id / _pdbx_entity_src_syn.organism_scientific / _struct_ref_seq_dif.details
Revision 1.7Aug 30, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.8Mar 13, 2024Group: Source and taxonomy / Structure summary / Category: entity / pdbx_entity_src_syn / Item: _entity.details
Revision 1.9Oct 30, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,8687
Polymers34,9972
Non-polymers8715
Water5,477304
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3730 Å2
ΔGint-97 kcal/mol
Surface area13700 Å2
MethodPISA
Unit cell
Length a, b, c (Å)53.945, 75.327, 80.984
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 Thrombin light chain / Coagulation factor II


Mass: 5280.812 Da / Num. of mol.: 1 / Fragment: residues 319-363
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: F2 / Plasmid: HPC4-PNUT / Cell line (production host): BHK-21 / Organ (production host): kidney / Production host: Cricetulus griseus (Chinese hamster) / References: UniProt: P00734, thrombin
#2: Protein Thrombin heavy chain / Coagulation factor II


Mass: 29716.090 Da / Num. of mol.: 1 / Fragment: residues 364-622 / Mutation: C191A, C220A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: F2 / Plasmid: HPC4-PNUT / Cell line (production host): BHK-21 / Organ (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, 308 molecules

#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Zn / Details: PPAK was chemically synthesized.
#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.: 304 / Source method: isolated from a natural source / Formula: H2O

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Details

Has protein modificationY
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: 2.34 Å3/Da / Density % sol: 47.49 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / pH: 6.3
Details: 20% PEG 3350 and 0.2 M Zinc Acetate, VAPOR DIFFUSION, HANGING DROP, temperature 295K, pH 6.3

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 14-BM-C / Wavelength: 0.9 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Aug 17, 2006
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9 Å / Relative weight: 1
ReflectionResolution: 1.8→40 Å / Num. all: 31582 / Num. obs: 31108 / % possible obs: 98.5 % / Observed criterion σ(F): -1 / Observed criterion σ(I): -1 / Redundancy: 6.6 % / Biso Wilson estimate: 17.8 Å2 / Rmerge(I) obs: 0.069 / Net I/σ(I): 22.6
Reflection shellResolution: 1.8→1.86 Å / Redundancy: 5.8 % / Rmerge(I) obs: 0.45 / Mean I/σ(I) obs: 3.2 / Num. unique all: 3097 / % possible all: 99.6

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Processing

Software
NameVersionClassification
CNS1.1refinement
ADSCQuantumdata collection
HKL-2000data reduction
SCALEPACKdata scaling
MOLREPfrom CCP4phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 1SHH

1shh


Resolution: 1.8→25.59 Å / Rfactor Rfree error: 0.005 / Data cutoff high absF: 350714.17 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
Details: The authors state that the atoms listed in remark 470 are missing because the residues were mutated to alanine during the refinement.
RfactorNum. reflection% reflectionSelection details
Rfree0.222 2113 7 %RANDOM
Rwork0.198 ---
obs0.198 30330 97.1 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 50.7162 Å2 / ksol: 0.391411 e/Å3
Displacement parametersBiso mean: 28.5 Å2
Baniso -1Baniso -2Baniso -3
1-1.13 Å20 Å20 Å2
2--0.42 Å20 Å2
3----1.55 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.23 Å0.2 Å
Luzzati d res low-5 Å
Luzzati sigma a0.18 Å0.14 Å
Refinement stepCycle: LAST / Resolution: 1.8→25.59 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2410 0 47 304 2761
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.021
X-RAY DIFFRACTIONc_angle_deg2
X-RAY DIFFRACTIONc_dihedral_angle_d26.5
X-RAY DIFFRACTIONc_improper_angle_d2.36
Refine LS restraints NCSNCS model details: CONSTR
LS refinement shellResolution: 1.8→1.91 Å / Rfactor Rfree error: 0.015 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.267 336 7 %
Rwork0.242 4487 -
obs--94.6 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1protein_rep-damino.paramprotein-damino.top
X-RAY DIFFRACTION2ion.paramion.top
X-RAY DIFFRACTION3water_rep.paramwater.top
X-RAY DIFFRACTION4ch2.paramnag.topo
X-RAY DIFFRACTION5nag.paramch2.topo

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