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- PDB-2x8d: Discovery of a Novel Class of triazolones as Checkpoint Kinase In... -

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Basic information

Entry
Database: PDB / ID: 2x8d
TitleDiscovery of a Novel Class of triazolones as Checkpoint Kinase Inhibitors - Hit to Lead Exploration
ComponentsSERINE/THREONINE-PROTEIN KINASE CHK1
KeywordsTRANSFERASE / NUCLEOTIDE-BINDING / CYTOSKELETON / PHOSPHOPROTEIN / ISOPEPTIDE BOND / CELL CYCLE / DNA DAMAGE / DNA REPAIR
Function / homology
Function and homology information


negative regulation of G0 to G1 transition / apoptotic process involved in development / histone H3T11 kinase activity / regulation of mitotic centrosome separation / negative regulation of mitotic nuclear division / mitotic G2/M transition checkpoint / inner cell mass cell proliferation / regulation of double-strand break repair via homologous recombination / nucleus organization / negative regulation of gene expression, epigenetic ...negative regulation of G0 to G1 transition / apoptotic process involved in development / histone H3T11 kinase activity / regulation of mitotic centrosome separation / negative regulation of mitotic nuclear division / mitotic G2/M transition checkpoint / inner cell mass cell proliferation / regulation of double-strand break repair via homologous recombination / nucleus organization / negative regulation of gene expression, epigenetic / Transcriptional Regulation by E2F6 / mitotic G2 DNA damage checkpoint signaling / Presynaptic phase of homologous DNA pairing and strand exchange / replicative senescence / peptidyl-threonine phosphorylation / signal transduction in response to DNA damage / Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex / Activation of ATR in response to replication stress / positive regulation of cell cycle / DNA damage checkpoint signaling / regulation of signal transduction by p53 class mediator / replication fork / condensed nuclear chromosome / TP53 Regulates Transcription of DNA Repair Genes / Ubiquitin-Mediated Degradation of Phosphorylated Cdc25A / cellular response to mechanical stimulus / Signaling by SCF-KIT / G2/M DNA damage checkpoint / G2/M transition of mitotic cell cycle / regulation of cell population proliferation / Processing of DNA double-strand break ends / Regulation of TP53 Activity through Phosphorylation / DNA replication / protein phosphorylation / non-specific serine/threonine protein kinase / protein kinase activity / chromatin remodeling / protein domain specific binding / protein serine kinase activity / DNA repair / intracellular membrane-bounded organelle / protein serine/threonine kinase activity / apoptotic process / DNA damage response / centrosome / chromatin / protein-containing complex / extracellular space / nucleoplasm / ATP binding / nucleus / cytoplasm / cytosol
Similarity search - Function
Checkpoint kinase 1, catalytic domain / 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, ATP binding site ...Checkpoint kinase 1, catalytic domain / 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, ATP binding site / Protein kinases ATP-binding region signature. / 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
5-METHYL[1,2,4]TRIAZOLO[4,3-A]QUINOLIN-1(2H)-ONE / Serine/threonine-protein kinase Chk1
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsRead, J.A. / Breed, J. / Haye, H. / McCall, E. / Rowsell, S. / Vallentine, A. / White, A.
CitationJournal: Bioorg.Med.Chem. / Year: 2010
Title: Discovery of a Novel Class of Triazolones as Checkpoint Kinase Inhibitors-Hit to Lead Exploration.
Authors: Oza, V. / Ashwell, S. / Brassil, P. / Breed, J. / Deng, C. / Ezhuthachan, J. / Haye, H. / Horn, C. / Janetka, J. / Lyne, P. / Newcombe, N. / Otterbien, L. / Pass, M. / Read, J.A. / Roswell, ...Authors: Oza, V. / Ashwell, S. / Brassil, P. / Breed, J. / Deng, C. / Ezhuthachan, J. / Haye, H. / Horn, C. / Janetka, J. / Lyne, P. / Newcombe, N. / Otterbien, L. / Pass, M. / Read, J.A. / Roswell, S. / Su, M. / Toader, D. / Yu, D. / Yu, Y. / Valentine, A. / Webborn, P. / White, A. / Zabludoff, S. / Zheng, X.
History
DepositionMar 8, 2010Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 11, 2010Provider: repository / Type: Initial release
Revision 1.1May 8, 2011Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3May 8, 2019Group: Data collection / Experimental preparation / Other
Category: database_PDB_rev / database_PDB_rev_record ...database_PDB_rev / database_PDB_rev_record / exptl_crystal_grow / pdbx_database_proc / pdbx_database_status
Item: _exptl_crystal_grow.method / _pdbx_database_status.recvd_author_approval
Revision 1.4Dec 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / 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 / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: SERINE/THREONINE-PROTEIN KINASE CHK1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,4344
Polymers33,0431
Non-polymers3913
Water6,341352
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)45.000, 66.236, 58.473
Angle α, β, γ (deg.)90.00, 94.59, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein SERINE/THREONINE-PROTEIN KINASE CHK1 / CHK1 CHECKPOINT KINASE


Mass: 33042.988 Da / Num. of mol.: 1 / Fragment: CHK1KD, RESIDUES 1-289
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: SPODOPTERA FRUGIPERDA (fall armyworm) / Strain (production host): SF9
References: UniProt: O14757, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-X8D / 5-METHYL[1,2,4]TRIAZOLO[4,3-A]QUINOLIN-1(2H)-ONE


Mass: 199.209 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C11H9N3O
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 352 / 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: 2.63 Å3/Da / Density % sol: 53.21 % / Description: NONE
Crystal growMethod: vapor diffusion, hanging drop / pH: 6.8
Details: HANGING DROP. 3UL PLUS 3UL PROTEIN: 7 MG/ML, 25MM TRIS PH7.5, 500MM NACL, 5% GLYCEROL. 5MM DTT WELL: 15-17% (W/V) PEG8000, 250MM AMMONIUM SULPHATE, 2% (V/V) GLYCEROL AND 100 MM SODIUM CACODYLATE PH 6.8

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SRS / Beamline: PX9.6 / Wavelength: 0.86
DetectorType: ADSC CCD / Detector: CCD / Date: Dec 5, 2001
RadiationMonochromator: SI111 / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.86 Å / Relative weight: 1
ReflectionResolution: 1.9→37.3 Å / Num. obs: 25219 / % possible obs: 93.8 % / Observed criterion σ(I): 2 / Redundancy: 2.5 % / Rmerge(I) obs: 0.1 / Net I/σ(I): 8.8
Reflection shellResolution: 1.9→2 Å / Redundancy: 1.9 % / Rmerge(I) obs: 0.24 / Mean I/σ(I) obs: 3 / % possible all: 64.6

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Processing

Software
NameVersionClassification
REFMAC5.5.0102refinement
MOSFLMdata reduction
SCALAdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1IA8

1ia8


Resolution: 1.9→37.3 Å / Cor.coef. Fo:Fc: 0.945 / Cor.coef. Fo:Fc free: 0.921 / SU B: 5.872 / SU ML: 0.079 / Cross valid method: THROUGHOUT / ESU R: 0.14 / ESU R Free: 0.126 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. U VALUES RESIDUAL ONLY. ATOM RECORD CONTAINS RESIDUAL B FACTORS ONLY.
RfactorNum. reflection% reflectionSelection details
Rfree0.19176 1270 5 %RANDOM
Rwork0.15998 ---
obs0.1616 23949 93.11 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 14.972 Å2
Baniso -1Baniso -2Baniso -3
1--0.17 Å20 Å2-0.58 Å2
2--0.63 Å20 Å2
3----0.55 Å2
Refinement stepCycle: LAST / Resolution: 1.9→37.3 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2235 0 25 352 2612
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0222328
X-RAY DIFFRACTIONr_bond_other_d0.0010.021597
X-RAY DIFFRACTIONr_angle_refined_deg1.2981.983160
X-RAY DIFFRACTIONr_angle_other_deg1.14433898
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.4085278
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.66124.364110
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.51615408
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.7051515
X-RAY DIFFRACTIONr_chiral_restr0.0750.2338
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0212581
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02459
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_it0.6061.51396
X-RAY DIFFRACTIONr_mcbond_other0.1191.5556
X-RAY DIFFRACTIONr_mcangle_it1.12522264
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.6793932
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it2.754.5896
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: 1.9→1.949 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.294 64 -
Rwork0.228 1139 -
obs--60.03 %
Refinement TLS params.Method: refined / Origin x: 5.3321 Å / Origin y: 0.146 Å / Origin z: 6.8034 Å
111213212223313233
T0.0121 Å2-0.002 Å20.0006 Å2-0.0034 Å20.0003 Å2--0.0213 Å2
L0.329 °2-0.087 °2-0.0877 °2-0.2437 °20.0237 °2--0.654 °2
S-0.0154 Å °0.0085 Å °-0.0111 Å °0.0284 Å °-0.0091 Å °0.0041 Å °0.0474 Å °0.0273 Å °0.0245 Å °

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