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- PDB-2w0j: Crystal structure of Chk2 in complex with NSC 109555, a specific ... -

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Basic information

Entry
Database: PDB / ID: 2w0j
TitleCrystal structure of Chk2 in complex with NSC 109555, a specific inhibitor
ComponentsSERINE/THREONINE-PROTEIN KINASE CHK2
KeywordsTRANSFERASE / CHK2 INHIBITOR / ONCOLOGY / KINASE / STRUCTURE-ASSISTED DRUG DESIGN / NUCLEOTIDE-BINDING / LI-FRAUMENI SYNDROME / SERINE/THREONINE-PROTEIN KINASE
Function / homology
Function and homology information


positive regulation of anoikis / mitotic DNA damage checkpoint signaling / cellular response to bisphenol A / regulation of autophagosome assembly / mitotic intra-S DNA damage checkpoint signaling / response to glycoside / thymocyte apoptotic process / cellular response to stress / regulation of protein catabolic process / negative regulation of DNA damage checkpoint ...positive regulation of anoikis / mitotic DNA damage checkpoint signaling / cellular response to bisphenol A / regulation of autophagosome assembly / mitotic intra-S DNA damage checkpoint signaling / response to glycoside / thymocyte apoptotic process / cellular response to stress / regulation of protein catabolic process / negative regulation of DNA damage checkpoint / replicative senescence / signal transduction in response to DNA damage / mitotic spindle assembly / intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex / DNA damage checkpoint signaling / regulation of signal transduction by p53 class mediator / DNA damage response, signal transduction by p53 class mediator / Ubiquitin-Mediated Degradation of Phosphorylated Cdc25A / protein catabolic process / Stabilization of p53 / cellular response to gamma radiation / G2/M DNA damage checkpoint / PML body / Regulation of TP53 Activity through Methylation / G2/M transition of mitotic cell cycle / cellular response to xenobiotic stimulus / intrinsic apoptotic signaling pathway in response to DNA damage / Regulation of TP53 Degradation / double-strand break repair / Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks / protein autophosphorylation / Regulation of TP53 Activity through Phosphorylation / protein phosphorylation / non-specific serine/threonine protein kinase / protein stabilization / cell division / protein serine kinase activity / protein serine/threonine kinase activity / DNA damage response / ubiquitin protein ligase binding / regulation of DNA-templated transcription / protein kinase binding / positive regulation of DNA-templated transcription / Golgi apparatus / protein homodimerization activity / nucleoplasm / ATP binding / metal ion binding / identical protein binding / nucleus / cytoplasm
Similarity search - Function
Forkhead associated domain / Forkhead-associated (FHA) domain profile. / FHA domain / Forkhead-associated (FHA) domain / SMAD/FHA domain superfamily / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Serine/threonine-protein kinase, active site ...Forkhead associated domain / Forkhead-associated (FHA) domain profile. / FHA domain / Forkhead-associated (FHA) domain / SMAD/FHA domain superfamily / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
NITRATE ION / 4,4'-DIACETYLDIPHENYLUREA-BIS(GUANYLHYDRAZONE) / Serine/threonine-protein kinase Chk2
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.05 Å
AuthorsLountos, G.T. / Tropea, J.E. / Zhang, D. / Jobson, A.G. / Pommier, Y. / Shoemaker, R.H. / Waugh, D.S.
Citation
Journal: Protein Sci. / Year: 2009
Title: Crystal Structure of Checkpoint Kinase 2 in Complex with Nsc 109555, a Potent and Selective Inhibitor
Authors: Lountos, G.T. / Tropea, J.E. / Zhang, D. / Jobson, A.G. / Pommier, Y. / Shoemaker, R.H. / Waugh, D.S.
#1: Journal: Mol.Pharmacol. / Year: 2007
Title: Identification of a Bis-Guanylhydrazone, 4,4'-Diacetyldiphenylurea-Bis(Guanylhydrazone) Nsc 109555, as a Novel Chemotype for Inhibition of Chk2 Kinase
Authors: Jobson, A.G. / Cardellina, J.H. / Scudiero, D. / Kondapaka, S. / Zhang, H. / Kim, H. / Shoemaker, R. / Pommier, Y.
History
DepositionAug 18, 2008Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 10, 2009Provider: repository / Type: Initial release
Revision 1.1May 8, 2011Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Dec 13, 2023Group: Data collection / Database references ...Data collection / Database references / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: SERINE/THREONINE-PROTEIN KINASE CHK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,0333
Polymers36,5621
Non-polymers4702
Water2,396133
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
Unit cell
Length a, b, c (Å)90.847, 90.847, 93.526
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number154
Space group name H-MP3221

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Components

#1: Protein SERINE/THREONINE-PROTEIN KINASE CHK2 / CHECKPOINT KINASE 2 / CDS1


Mass: 36562.238 Da / Num. of mol.: 1 / Fragment: CATALYTIC DOMAIN, RESIDUES 210-531
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: PDZ1927 / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21-CODONPLUS (DE3)RIL
References: UniProt: O96017, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-ZAT / 4,4'-DIACETYLDIPHENYLUREA-BIS(GUANYLHYDRAZONE)


Mass: 408.460 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H24N10O
#3: Chemical ChemComp-NO3 / NITRATE ION


Mass: 62.005 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: NO3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 133 / 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: 3.1 Å3/Da / Density % sol: 59.7 % / Description: NONE
Crystal growpH: 7.8
Details: 0.1 M HEPES PH 7.8, 0.2 M MAGNESIUM NITRATE, 14% W/V PEG3350, 16% V/V ETHYLENE GLYCOL. PROTEIN WAS INCUBATED WITH 1MM INHIBITOR PRIOR TO CRYSTALLIZATION

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-ID / Wavelength: 1
DetectorType: MARRESEARCH / Detector: CCD / Date: Jun 10, 2007
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.05→50 Å / Num. obs: 28962 / % possible obs: 99.9 % / Observed criterion σ(I): 2 / Redundancy: 7.4 % / Rmerge(I) obs: 0.06 / Net I/σ(I): 25.9
Reflection shellResolution: 2.05→2.12 Å / Redundancy: 7.3 % / Rmerge(I) obs: 0.54 / Mean I/σ(I) obs: 4.1 / % possible all: 99.9

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Processing

Software
NameVersionClassification
REFMAC5.4.0057refinement
HKL-3000data reduction
SCALEPACKdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2CN5

2cn5


Resolution: 2.05→50 Å / Cor.coef. Fo:Fc: 0.951 / Cor.coef. Fo:Fc free: 0.943 / SU B: 4.323 / SU ML: 0.118 / Cross valid method: THROUGHOUT / ESU R: 0.168 / ESU R Free: 0.154 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.246 1432 5 %RANDOM
Rwork0.215 ---
obs0.217 26962 99.9 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 34.99 Å2
Baniso -1Baniso -2Baniso -3
1-0.32 Å20.16 Å20 Å2
2--0.32 Å20 Å2
3----0.49 Å2
Refinement stepCycle: LAST / Resolution: 2.05→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2252 0 34 133 2419
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.0222326
X-RAY DIFFRACTIONr_bond_other_d0.0030.021609
X-RAY DIFFRACTIONr_angle_refined_deg1.561.9993133
X-RAY DIFFRACTIONr_angle_other_deg0.9373.0023931
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.5775275
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.75924.79698
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.42715441
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.221510
X-RAY DIFFRACTIONr_chiral_restr0.0930.2356
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0212487
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02442
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_it1.041.51396
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.89822259
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it2.4683930
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it4.074.5874
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: 2.05→2.1 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rfree0.295 104
Rwork0.241 1998

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