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- PDB-2yex: Synthesis and evaluation of triazolones as checkpoint kinase 1 in... -

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Entry
Database: PDB / ID: 2yex
TitleSynthesis and evaluation of triazolones as checkpoint kinase 1 inhibitors
ComponentsSERINE/THREONINE-PROTEIN KINASE CHK1
KeywordsTRANSFERASE / CELL CYCLE / CHK
Function / homology
Function and homology information


negative regulation of mitotic nuclear division / negative regulation of G0 to G1 transition / histone H3T11 kinase activity / regulation of mitotic centrosome separation / mitotic G2/M transition checkpoint / regulation of double-strand break repair via homologous recombination / peptidyl-threonine phosphorylation / negative regulation of gene expression, epigenetic / mitotic G2 DNA damage checkpoint signaling / Transcriptional Regulation by E2F6 ...negative regulation of mitotic nuclear division / negative regulation of G0 to G1 transition / histone H3T11 kinase activity / regulation of mitotic centrosome separation / mitotic G2/M transition checkpoint / regulation of double-strand break repair via homologous recombination / peptidyl-threonine phosphorylation / negative regulation of gene expression, epigenetic / mitotic G2 DNA damage checkpoint signaling / Transcriptional Regulation by E2F6 / replicative senescence / Presynaptic phase of homologous DNA pairing and strand exchange / Activation of ATR in response to replication stress / Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex / DNA damage checkpoint signaling / signal transduction in response to DNA damage / positive regulation of cell cycle / replication fork / regulation of signal transduction by p53 class mediator / condensed nuclear chromosome / TP53 Regulates Transcription of DNA Repair Genes / cellular response to mechanical stimulus / Signaling by SCF-KIT / G2/M DNA damage checkpoint / Ubiquitin-Mediated Degradation of Phosphorylated Cdc25A / Processing of DNA double-strand break ends / Regulation of TP53 Activity through Phosphorylation / DNA replication / protein kinase activity / protein phosphorylation / non-specific serine/threonine protein kinase / chromatin remodeling / protein domain specific binding / protein serine kinase activity / DNA repair / protein serine/threonine kinase activity / apoptotic process / centrosome / DNA damage response / chromatin / protein-containing complex / : / nucleoplasm / ATP binding / nucleus / cytosol / cytoplasm
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
Chem-YEX / Serine/threonine-protein kinase Chk1
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.3 Å
AuthorsRead, J.A. / Breed, J. / Haye, H. / McCall, E. / Vallentine, A. / White, A.
Citation
Journal: Bioorg.Med.Chem.Lett. / Year: 2012
Title: Synthesis and Evaluation of Triazolones as Checkpoint Kinase 1 Inhibitors.
Authors: Oza, V. / Ashwell, S. / Brassil, P. / Breed, J. / Ezhuthachan, J. / Deng, C. / Grondine, M. / Horn, C. / Liu, D. / Lyne, P. / Newcombe, N. / Pass, M. / Read, J. / Su, M. / Toader, D. / Yu, D. ...Authors: Oza, V. / Ashwell, S. / Brassil, P. / Breed, J. / Ezhuthachan, J. / Deng, C. / Grondine, M. / Horn, C. / Liu, D. / Lyne, P. / Newcombe, N. / Pass, M. / Read, J. / Su, M. / Toader, D. / Yu, D. / Yu, Y. / Zabludoff, S.
#1: Journal: Bioorg.Med.Chem.Lett. / 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. / Roswell, S. ...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. / Roswell, S. / Su, M. / Toader, D. / Yu, D. / Yu, Y. / Valentine, A. / Webborn, P. / White, A. / Zabludoff, S. / Zheng, X.
History
DepositionMar 31, 2011Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 14, 2012Provider: repository / Type: Initial release
Revision 1.1May 8, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / 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)32,84610
Polymers31,8411
Non-polymers1,0059
Water8,071448
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)41.352, 70.770, 104.327
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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


Mass: 31840.738 Da / Num. of mol.: 1 / Fragment: CHK1KD, RESIDUES 1-276
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-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C3H8O3
#3: Chemical ChemComp-YEX / 5-METHYL-8-(1H-PYRROL-2-YL)[1,2,4]TRIAZOLO[4,3-A]QUINOLIN-1(2H)-ONE


Mass: 264.282 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H12N4O
#4: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 448 / 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: 2.46 Å3/Da / Density % sol: 50 % / Description: NONE
Crystal growpH: 7.5 / Details: pH 7.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID29 / Wavelength: 1.265
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Apr 10, 2003 / Details: MIRRORS
RadiationMonochromator: SI111 / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.265 Å / Relative weight: 1
ReflectionResolution: 1.3→25 Å / Num. obs: 62083 / % possible obs: 83.6 % / Observed criterion σ(I): 2 / Redundancy: 2.8 % / Biso Wilson estimate: 11.2 Å2 / Rmerge(I) obs: 0.06 / Net I/σ(I): 13.3
Reflection shellResolution: 1.3→1.37 Å / Redundancy: 1.7 % / Rmerge(I) obs: 0.52 / Mean I/σ(I) obs: 1.7 / % possible all: 34.3

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Processing

Software
NameVersionClassification
REFMAC5.5.0110refinement
MOSFLMdata reduction
SCALAdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.3→24.92 Å / Cor.coef. Fo:Fc: 0.973 / Cor.coef. Fo:Fc free: 0.962 / SU B: 1.359 / SU ML: 0.026 / Cross valid method: THROUGHOUT / ESU R: 0.053 / ESU R Free: 0.05 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.16415 3143 5.1 %RANDOM
Rwork0.13352 ---
obs0.13503 58940 81.59 %-
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: 8.814 Å2
Baniso -1Baniso -2Baniso -3
1--0.42 Å20 Å20 Å2
2--0.74 Å20 Å2
3----0.33 Å2
Refinement stepCycle: LAST / Resolution: 1.3→24.92 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2151 0 67 448 2666
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0222306
X-RAY DIFFRACTIONr_bond_other_d0.0020.021581
X-RAY DIFFRACTIONr_angle_refined_deg1.5071.9883134
X-RAY DIFFRACTIONr_angle_other_deg0.93433861
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.3835282
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.93124.667105
X-RAY DIFFRACTIONr_dihedral_angle_3_deg9.92215387
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.6261512
X-RAY DIFFRACTIONr_chiral_restr0.0880.2334
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.0212570
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02455
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_it1.1441.51375
X-RAY DIFFRACTIONr_mcbond_other0.4391.5546
X-RAY DIFFRACTIONr_mcangle_it1.77622231
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it2.633931
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it3.7954.5899
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr1.15933887
X-RAY DIFFRACTIONr_sphericity_free5.5783449
X-RAY DIFFRACTIONr_sphericity_bonded2.29433832
LS refinement shellResolution: 1.3→1.334 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.292 78 -
Rwork0.211 1458 -
obs--27.76 %
Refinement TLS params.Method: refined / Origin x: 14.0183 Å / Origin y: 34.4825 Å / Origin z: 16.5371 Å
111213212223313233
T0.0096 Å20.0011 Å20.0055 Å2-0.0004 Å20.0008 Å2--0.0082 Å2
L0.2212 °20.0183 °20.0732 °2-0.0522 °2-0.0135 °2--0.1886 °2
S-0.0033 Å °0.0018 Å °0.0069 Å °0.0044 Å °0.0021 Å °-0.0027 Å °-0.0104 Å °-0.0062 Å °0.0012 Å °

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