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

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Basic information

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


negative regulation of G0 to G1 transition / apoptotic process involved in development / histone H3T11 kinase activity / negative regulation of DNA biosynthetic process / mitotic G2/M transition checkpoint / negative regulation of mitotic nuclear division / regulation of mitotic centrosome separation / inner cell mass cell proliferation / regulation of double-strand break repair via homologous recombination / nucleus organization ...negative regulation of G0 to G1 transition / apoptotic process involved in development / histone H3T11 kinase activity / negative regulation of DNA biosynthetic process / mitotic G2/M transition checkpoint / negative regulation of mitotic nuclear division / regulation of mitotic centrosome separation / inner cell mass cell proliferation / regulation of double-strand break repair via homologous recombination / nucleus organization / negative regulation of gene expression, epigenetic / cellular response to caffeine / mitotic G2 DNA damage checkpoint signaling / Transcriptional Regulation by E2F6 / Presynaptic phase of homologous DNA pairing and strand exchange / replicative senescence / 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 / regulation of signal transduction by p53 class mediator / DNA damage checkpoint signaling / condensed nuclear chromosome / replication fork / TP53 Regulates Transcription of DNA Repair Genes / Ubiquitin Mediated Degradation of Phosphorylated Cdc25A / peptidyl-threonine phosphorylation / G2/M DNA damage checkpoint / Signaling by SCF-KIT / cellular response to mechanical stimulus / 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 / non-specific serine/threonine protein kinase / protein kinase activity / chromatin remodeling / protein phosphorylation / protein domain specific binding / intracellular membrane-bounded organelle / protein serine kinase activity / DNA repair / protein serine/threonine kinase activity / centrosome / DNA damage response / chromatin / apoptotic process / protein-containing complex / extracellular space / nucleoplasm / ATP binding / nucleus / cytosol / cytoplasm
Similarity search - Function
Checkpoint kinase 1, catalytic domain / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; 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 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; 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-TQ1 / Serine/threonine-protein kinase Chk1
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.83 Å
AuthorsRead, J.A. / Breed, J. / Haye, H. / McCall, E. / Vallentine, A. / White, A. / Otterbein, L.
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 30, 2011Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 14, 2012Provider: repository / Type: Initial release
Revision 1.1Apr 4, 2018Group: Data collection / Category: diffrn_source / Item: _diffrn_source.type
Revision 1.2May 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)32,5899
Polymers31,8411
Non-polymers7498
Water7,332407
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)41.160, 69.920, 103.500
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) / Cell line (production host): SF9 / Production host: SPODOPTERA FRUGIPERDA (fall armyworm)
References: UniProt: O14757, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-TQ1 / 5-(HYDROXYMETHYL)-8-(1H-PYRROL-2-YL)-2H-[1,2,4]TRIAZOLO[4,3-A]QUINOLIN-1-ONE


Mass: 280.281 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H12N4O2
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#4: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 407 / 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: 2.4 Å3/Da / Density % sol: 48.74 % / Description: NONE
Crystal growpH: 7.5 / Details: pH 7.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E / Wavelength: 1.5418
DetectorType: RIGAKU CCD / Detector: CCD / Date: Oct 1, 2009 / Details: MIRRORS
RadiationMonochromator: NI FILTER / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.83→103 Å / Num. obs: 22780 / % possible obs: 83.9 % / Observed criterion σ(I): 2 / Redundancy: 5.6 % / Biso Wilson estimate: 7.58 Å2 / Rmerge(I) obs: 0.03 / Net I/σ(I): 36.5
Reflection shellResolution: 1.83→1.93 Å / Redundancy: 1.7 % / Rmerge(I) obs: 0.05 / Mean I/σ(I) obs: 11.9 / % possible all: 25

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Processing

Software
NameVersionClassification
REFMAC5.5.0110refinement
MOSFLMdata reduction
SCALAdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.83→57.94 Å / Cor.coef. Fo:Fc: 0.957 / Cor.coef. Fo:Fc free: 0.94 / SU B: 4.343 / SU ML: 0.063 / Cross valid method: THROUGHOUT / ESU R: 0.139 / ESU R Free: 0.12 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.17538 1121 4.9 %RANDOM
Rwork0.14519 ---
obs0.14667 21599 83.91 %-
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: 14.433 Å2
Baniso -1Baniso -2Baniso -3
1--0.3 Å20 Å20 Å2
2--0.6 Å20 Å2
3----0.3 Å2
Refinement stepCycle: LAST / Resolution: 1.83→57.94 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2153 0 50 407 2610
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0222257
X-RAY DIFFRACTIONr_bond_other_d0.0010.021555
X-RAY DIFFRACTIONr_angle_refined_deg1.281.9823055
X-RAY DIFFRACTIONr_angle_other_deg1.12633785
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.3435267
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.65424.34106
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.14615384
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.6961514
X-RAY DIFFRACTIONr_chiral_restr0.0950.2327
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0212497
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02450
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_it0.4091.51340
X-RAY DIFFRACTIONr_mcbond_other0.0751.5534
X-RAY DIFFRACTIONr_mcangle_it0.80522172
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.2333917
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it2.0754.5883
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: 1.831→1.878 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.357 7 -
Rwork0.155 239 -
obs--12.47 %
Refinement TLS params.Method: refined / Origin x: 13.9497 Å / Origin y: 33.9223 Å / Origin z: 16.2646 Å
111213212223313233
T0.0126 Å20.0025 Å20.0061 Å2-0.0005 Å20.0011 Å2--0.0141 Å2
L0.2471 °20.0357 °20.0812 °2-0.0649 °2-0.0244 °2--0.331 °2
S-0.0022 Å °-0.0028 Å °0.0154 Å °0.004 Å °0.0016 Å °-0.0012 Å °-0.0193 Å °-0.0056 Å °0.0006 Å °

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