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- PDB-5dls: Identification of Novel, in vivo Active Chk1 Inhibitors Utilizing... -

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Entry
Database: PDB / ID: 5dls
TitleIdentification of Novel, in vivo Active Chk1 Inhibitors Utilizing Structure Guided Drug Design
ComponentsSerine/threonine-protein kinase Chk1
KeywordsTRANSFERASE / Chk1 / V158411 / fragment / kinase
Function / homology
Function and homology information


negative regulation of G0 to G1 transition / apoptotic process involved in development / negative regulation of DNA biosynthetic process / 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 / negative regulation of gene expression, epigenetic / nucleus organization ...negative regulation of G0 to G1 transition / apoptotic process involved in development / negative regulation of DNA biosynthetic process / 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 / negative regulation of gene expression, epigenetic / nucleus organization / mitotic G2 DNA damage checkpoint signaling / Transcriptional Regulation by E2F6 / cellular response to caffeine / 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 / Ubiquitin-Mediated Degradation of Phosphorylated Cdc25A / DNA damage checkpoint signaling / histone H4S1 kinase activity / : / histone H3S57 kinase activity / histone H2BS14 kinase activity / histone H3S28 kinase activity / histone H2AS1 kinase activity / histone H3T6 kinase activity / regulation of signal transduction by p53 class mediator / condensed nuclear chromosome / ribosomal protein S6 kinase activity / histone H2AT120 kinase activity / histone H2BS36 kinase activity / eukaryotic translation initiation factor 2alpha kinase activity / replication fork / Rho-dependent protein serine/threonine kinase activity / histone H3S10 kinase activity / AMP-activated protein kinase activity / histone H3T11 kinase activity / histone H3T3 kinase activity / 3-phosphoinositide-dependent protein kinase activity / histone H3T45 kinase activity / DNA-dependent protein kinase activity / histone H2AXS139 kinase activity / TP53 Regulates Transcription of DNA Repair Genes / Signaling by SCF-KIT / G2/M DNA damage checkpoint / cellular response to mechanical stimulus / G2/M transition of mitotic cell cycle / Processing of DNA double-strand break ends / regulation of cell population proliferation / Regulation of TP53 Activity through Phosphorylation / DNA replication / non-specific serine/threonine protein kinase / protein kinase activity / protein phosphorylation / chromatin remodeling / protein domain specific binding / protein serine kinase activity / DNA repair / protein serine/threonine kinase activity / intracellular membrane-bounded organelle / apoptotic process / centrosome / DNA damage response / chromatin / protein-containing complex / extracellular space / 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-5CV / Serine/threonine-protein kinase Chk1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.15 Å
AuthorsMassey, A.J. / Stokes, S. / Browne, H. / Foloppe, N. / Fiumana, A. / Scrace, S. / Fallowfield, M. / Bedford, S. / Webb, P. / Baker, L.M. ...Massey, A.J. / Stokes, S. / Browne, H. / Foloppe, N. / Fiumana, A. / Scrace, S. / Fallowfield, M. / Bedford, S. / Webb, P. / Baker, L.M. / Christie, M. / Drysdale, M.J. / Wood, M.
CitationJournal: Oncotarget / Year: 2015
Title: Identification of novel, in vivo active Chk1 inhibitors utilizing structure guided drug design.
Authors: Massey, A.J. / Stokes, S. / Browne, H. / Foloppe, N. / Fiumana, A. / Scrace, S. / Fallowfield, M. / Bedford, S. / Webb, P. / Baker, L. / Christie, M. / Drysdale, M.J. / Wood, M.
History
DepositionSep 7, 2015Deposition site: RCSB / Processing site: PDBE
Revision 1.0Oct 14, 2015Provider: repository / Type: Initial release
Revision 1.1Nov 25, 2015Group: Database references
Revision 1.2Jan 10, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)34,7833
Polymers34,1481
Non-polymers6352
Water1,964109
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area230 Å2
ΔGint-18 kcal/mol
Surface area12700 Å2
MethodPISA
Unit cell
Length a, b, c (Å)45.032, 65.713, 58.392
Angle α, β, γ (deg.)90.00, 95.14, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Serine/threonine-protein kinase Chk1 / CHK1 checkpoint homolog / Cell cycle checkpoint kinase / Checkpoint kinase-1


Mass: 34148.148 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CHEK1, CHK1 / Plasmid: PFASTBAC1 / Details (production host): CHK1 1-289 C8H / Cell line (production host): SF9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: O14757, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-5CV / 1-benzyl-N-(5-{5-[3-(dimethylamino)-2,2-dimethylpropoxy]-1H-indol-2-yl}-6-oxo-1,6-dihydropyridin-3-yl)-1H-pyrazole-4-carboxamide


Mass: 538.640 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C31H34N6O3
#3: Chemical ChemComp-SO4 / SULFATE ION


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


Mass: 18.015 Da / Num. of mol.: 109 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.8 Å3/Da / Density % sol: 55.67 % / Description: Rods
Crystal growTemperature: 292 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 10-15% PEG8K, 0.1 M Hepes pH 7.5, and 15% (v/v) 2-propanol.
PH range: 7.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I02 / Wavelength: 0.979 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Dec 3, 2008
RadiationMonochromator: Si111 double crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2.15→28.6 Å / Num. all: 17905 / Num. obs: 17876 / % possible obs: 96.4 % / Redundancy: 2.5 % / Rmerge(I) obs: 0.068 / Net I/σ(I): 5.5
Reflection shellResolution: 2.15→2.23 Å / Redundancy: 2.3 % / Rmerge(I) obs: 0.551 / Mean I/σ(I) obs: 4.7 / % possible all: 84

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Processing

Software
NameVersionClassification
REFMAC5.8.0124refinement
HKL-2000data reduction
HKL-2000data scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1IA8

1ia8


Resolution: 2.15→28.6 Å / Cor.coef. Fo:Fc: 0.97 / Cor.coef. Fo:Fc free: 0.948 / SU B: 5.842 / SU ML: 0.143 / Cross valid method: THROUGHOUT / ESU R: 0.189 / ESU R Free: 0.177 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.22163 923 5.2 %RANDOM
Rwork0.16507 ---
obs0.16802 16982 96.25 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 50.399 Å2
Baniso -1Baniso -2Baniso -3
1--1.61 Å20 Å2-0.66 Å2
2--1.57 Å20 Å2
3---0.15 Å2
Refinement stepCycle: 1 / Resolution: 2.15→28.6 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2044 0 45 109 2198
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0170.0192140
X-RAY DIFFRACTIONr_bond_other_d0.0020.022026
X-RAY DIFFRACTIONr_angle_refined_deg1.8981.9862909
X-RAY DIFFRACTIONr_angle_other_deg1.13.0034616
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.6725255
X-RAY DIFFRACTIONr_dihedral_angle_2_deg39.78924.4998
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.69515357
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.7831512
X-RAY DIFFRACTIONr_chiral_restr0.1220.2314
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.0212388
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02472
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_it3.9664.8721026
X-RAY DIFFRACTIONr_mcbond_other3.9634.8691025
X-RAY DIFFRACTIONr_mcangle_it5.6627.2791279
X-RAY DIFFRACTIONr_mcangle_other5.6627.2821280
X-RAY DIFFRACTIONr_scbond_it5.1565.2341114
X-RAY DIFFRACTIONr_scbond_other4.9655.2161111
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other7.5327.6191624
X-RAY DIFFRACTIONr_long_range_B_refined9.33238.2532508
X-RAY DIFFRACTIONr_long_range_B_other9.27738.1622467
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.148→2.204 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.344 66 -
Rwork0.266 1044 -
obs--81.98 %

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