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- PDB-2x8i: Discovery of a Novel Class of triazolones as Checkpoint Kinase In... -

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Basic information

Entry
Database: PDB / ID: 2x8i
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 / negative regulation of DNA biosynthetic process / negative regulation of mitotic nuclear division / mitotic G2/M transition checkpoint / regulation of mitotic centrosome separation / nucleus organization / inner cell mass cell proliferation / negative regulation of gene expression, epigenetic ...negative regulation of G0 to G1 transition / apoptotic process involved in development / histone H3T11 kinase activity / negative regulation of DNA biosynthetic process / negative regulation of mitotic nuclear division / mitotic G2/M transition checkpoint / regulation of mitotic centrosome separation / nucleus organization / inner cell mass cell proliferation / negative regulation of gene expression, epigenetic / regulation of double-strand break repair via homologous recombination / cellular response to caffeine / Transcriptional Regulation by E2F6 / mitotic G2 DNA damage checkpoint signaling / Presynaptic phase of homologous DNA pairing and strand exchange / replicative senescence / Activation of ATR in response to replication stress / positive regulation of cell cycle / Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex / signal transduction in response to DNA damage / replication fork / DNA damage checkpoint signaling / condensed nuclear chromosome / regulation of signal transduction by p53 class mediator / Ubiquitin Mediated Degradation of Phosphorylated Cdc25A / TP53 Regulates Transcription of DNA Repair Genes / 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 / intracellular signal transduction / chromatin remodeling / protein domain specific binding / protein phosphorylation / DNA repair / protein serine kinase activity / intracellular membrane-bounded organelle / protein serine/threonine kinase activity / centrosome / apoptotic process / DNA damage response / chromatin / 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-X8I / Serine/threonine-protein kinase Chk1
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.92 Å
AuthorsRead, J.A. / Breed, J. / Haye, H. / McCall, E. / Otterbein, L. / 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 9, 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 1.4Jul 24, 2019Group: Data collection / Category: diffrn_source / Item: _diffrn_source.pdbx_synchrotron_site
Revision 1.5Dec 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)33,6195
Polymers33,0431
Non-polymers5764
Water4,342241
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)41.255, 70.900, 104.241
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: 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-X8I / 7-(3-hydroxyphenyl)-5-methyl[1,2,4]triazolo[4,3-a]quinolin-1(2H)-one


Mass: 291.304 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H13N3O2
#3: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 241 / 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: 2.28 Å3/Da / Density % sol: 45.65 % / Description: NONE
Crystal growMethod: vapor diffusion, hanging drop / pH: 6.5
Details: HANGING DROP 3 UL PLUS 3UL PROTEIN: 7MG/ML, 2MM COMPOUND, 25MM TRIS PH7.5, 500MM NACL, 5% GLYCEROL. 5MM DTT WELL: 16-22% (W/V) PEG3350, 150MM AMMONIUM SULPHATE AND 100 MM BES PH 6.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: EMBL/DESY, HAMBURG / Beamline: X13 / Wavelength: 0.8019
DetectorType: MARRESEARCH / Detector: CCD / Date: Aug 20, 2002
RadiationMonochromator: SI111 / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.8019 Å / Relative weight: 1
ReflectionResolution: 1.92→31.16 Å / Num. obs: 22530 / % possible obs: 94.3 % / Observed criterion σ(I): 2 / Redundancy: 5.8 % / Rmerge(I) obs: 0.08 / Net I/σ(I): 14
Reflection shellResolution: 1.92→2.02 Å / Redundancy: 5.4 % / Rmerge(I) obs: 0.29 / Mean I/σ(I) obs: 5.6 / % possible all: 89.4

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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 2X8D

2x8d


Resolution: 1.92→31.16 Å / Cor.coef. Fo:Fc: 0.942 / Cor.coef. Fo:Fc free: 0.929 / SU B: 6.927 / SU ML: 0.094 / Cross valid method: THROUGHOUT / ESU R: 0.168 / ESU R Free: 0.149 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. ATOM RECORD CONTAINS RESIDUAL B FACTORS ONLY
RfactorNum. reflection% reflectionSelection details
Rfree0.22368 1147 5.1 %RANDOM
Rwork0.1876 ---
obs0.1894 21383 93.59 %-
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: 15.693 Å2
Baniso -1Baniso -2Baniso -3
1--1.49 Å20 Å20 Å2
2--1.65 Å20 Å2
3----0.17 Å2
Refinement stepCycle: LAST / Resolution: 1.92→31.16 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2091 0 38 241 2370
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0222199
X-RAY DIFFRACTIONr_bond_other_d0.0010.021479
X-RAY DIFFRACTIONr_angle_refined_deg1.2691.982988
X-RAY DIFFRACTIONr_angle_other_deg1.82533620
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.1585261
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.47924.563103
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.34415377
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.7191512
X-RAY DIFFRACTIONr_chiral_restr0.1570.2321
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0212445
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02436
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_it0.5031.51309
X-RAY DIFFRACTIONr_mcbond_other0.0771.5523
X-RAY DIFFRACTIONr_mcangle_it0.93722124
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.2753890
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it2.1244.5864
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: 1.92→1.97 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.244 89 -
Rwork0.21 1377 -
obs--83.53 %
Refinement TLS params.Method: refined / Origin x: 14.3948 Å / Origin y: 1.0427 Å / Origin z: 34.413 Å
111213212223313233
T0.0557 Å2-0.004 Å2-0.0139 Å2-0.0038 Å20.0006 Å2--0.037 Å2
L0.9197 °2-0.0439 °2-0.2134 °2-0.1045 °20.0942 °2--0.5992 °2
S-0.0127 Å °-0.0551 Å °-0.0071 Å °-0.0251 Å °0.0021 Å °-0.005 Å °0.0403 Å °0.0069 Å °0.0107 Å °

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