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- PDB-2brb: Structure-based Design of Novel Chk1 Inhibitors: Insights into Hy... -

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Basic information

Entry
Database: PDB / ID: 2brb
TitleStructure-based Design of Novel Chk1 Inhibitors: Insights into Hydrogen Bonding and Protein-Ligand Affinity
ComponentsSERINE/THREONINE-PROTEIN KINASE CHK1
KeywordsTRANSFERASE / DRUG DESIGN / FURANOPYRIMIDINE / MOLECULAR RECOGNITION / ONCOLOGY / PYRROLOPYRIMIDINE
Function / homology
Function and homology information


negative regulation of G0 to G1 transition / apoptotic process involved in development / negative regulation of DNA biosynthetic process / negative regulation of mitotic nuclear division / mitotic G2/M transition checkpoint / regulation of mitotic centrosome separation / 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 / negative regulation of mitotic nuclear division / mitotic G2/M transition checkpoint / regulation of mitotic centrosome separation / inner cell mass cell proliferation / regulation of double-strand break repair via homologous recombination / negative regulation of gene expression, epigenetic / nucleus organization / 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 / DNA damage checkpoint signaling / regulation of signal transduction by p53 class mediator / condensed nuclear chromosome / replication fork / TP53 Regulates Transcription of DNA Repair Genes / peptidyl-threonine phosphorylation / Ubiquitin Mediated Degradation of Phosphorylated Cdc25A / Signaling by SCF-KIT / G2/M DNA damage checkpoint / 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 / eukaryotic translation initiation factor 2alpha kinase activity / DNA replication / 3-phosphoinositide-dependent protein kinase activity / DNA-dependent protein kinase activity / ribosomal protein S6 kinase activity / histone H3S10 kinase activity / histone H2AXS139 kinase activity / histone H3S28 kinase activity / histone H4S1 kinase activity / histone H2BS14 kinase activity / histone H3T3 kinase activity / histone H2AS121 kinase activity / histone H2BS36 kinase activity / histone H3S57 kinase activity / histone H2AT120 kinase activity / AMP-activated protein kinase activity / Rho-dependent protein serine/threonine kinase activity / histone H3T6 kinase activity / histone H2AS1 kinase activity / histone H3T11 kinase activity / histone H3T45 kinase activity / non-specific serine/threonine protein kinase / protein kinase activity / protein phosphorylation / chromatin remodeling / protein domain specific binding / intracellular membrane-bounded organelle / protein serine kinase activity / DNA repair / 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 / Phosphorylase Kinase; domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site ...Checkpoint kinase 1, catalytic domain / Phosphorylase Kinase; domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / 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-PFQ / Serine/threonine-protein kinase Chk1
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsFoloppe, N. / Fisher, L.M. / Howes, R. / Kierstan, P. / Potter, A. / Robertson, A.G.S. / Surgenor, A.E.
CitationJournal: J.Med.Chem. / Year: 2005
Title: Structure-Based Design of Novel Chk1 Inhibitors: Insights Into Hydrogen Bonding and Protein-Ligand Affinity.
Authors: Foloppe, N. / Fisher, L.M. / Howes, R. / Kierstan, P. / Potter, A. / Robertson, A.G.S. / Surgenor, A.E.
History
DepositionMay 4, 2005Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 12, 2005Provider: repository / Type: Initial release
Revision 1.1May 8, 2011Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Dec 13, 2023Group: Data collection / Database references ...Data collection / Database references / 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
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)34,5763
Polymers34,1481
Non-polymers4272
Water4,107228
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
Unit cell
Length a, b, c (Å)44.993, 65.770, 58.360
Angle α, β, γ (deg.)90.00, 94.29, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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


Mass: 34148.148 Da / Num. of mol.: 1 / Fragment: N-TERMINAL KINASE DOMAIN, RESIDUES 1-289
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: PFASTBAC1/CHK1 1-289 C8H / Cell line (production host): SF9 / Production host: SPODOPTERA FRUGIPERDA (fall armyworm) / References: UniProt: O14757, EC: 2.7.1.37
#2: Chemical ChemComp-PFQ / 2-[(5,6-DIPHENYLFURO[2,3-D]PYRIMIDIN-4-YL)AMINO]ETHANOL


Mass: 331.368 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H17N3O2
#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.: 228 / 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: 2.9 Å3/Da / Density % sol: 56.6 %
Crystal growpH: 7.5 / Details: pH 7.50

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID29 / Wavelength: 0.9757
DetectorDetector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9757 Å / Relative weight: 1
ReflectionResolution: 2.1→30 Å / Num. obs: 20050 / % possible obs: 96.6 % / Observed criterion σ(I): 2 / Redundancy: 4 % / Rmerge(I) obs: 0.08 / Net I/σ(I): 13
Reflection shellResolution: 2.1→2.18 Å / Redundancy: 2 % / Rmerge(I) obs: 0.44 / Mean I/σ(I) obs: 2.7 / % possible all: 83.2

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Processing

Software
NameVersionClassification
REFMAC5.1.24refinement
DENZOdata reduction
SCALEPACKdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1IA8

1ia8


Resolution: 2.1→57.74 Å / Cor.coef. Fo:Fc: 0.925 / Cor.coef. Fo:Fc free: 0.909 / SU B: 5.661 / SU ML: 0.153 / Cross valid method: THROUGHOUT / ESU R: 0.272 / ESU R Free: 0.211 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.272 1004 5.1 %RANDOM
Rwork0.241 ---
obs0.243 18612 97.9 %-
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: 38.67 Å2
Baniso -1Baniso -2Baniso -3
1--1.5 Å20 Å2-0.12 Å2
2--0.04 Å20 Å2
3---1.44 Å2
Refinement stepCycle: LAST / Resolution: 2.1→57.74 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2184 0 30 228 2442
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0212268
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg0.991.9753074
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg3.925270
X-RAY DIFFRACTIONr_dihedral_angle_2_deg
X-RAY DIFFRACTIONr_dihedral_angle_3_deg
X-RAY DIFFRACTIONr_dihedral_angle_4_deg
X-RAY DIFFRACTIONr_chiral_restr0.0660.2328
X-RAY DIFFRACTIONr_gen_planes_refined0.0020.021725
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.1590.21026
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.070.2209
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1140.242
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.0630.222
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.4611.51358
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it0.83722192
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it0.6913910
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it1.3044.5882
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: 2.1→2.15 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rfree0.331 70
Rwork0.297 1344

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