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

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Basic information

Entry
Database: PDB / ID: 2brn
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 / ATP-BINDING / CELL CYCLE / DNA DAMAGE / KINASE / NUCLEAR PROTEIN / PHOSPHORYLATION / POLYMORPHISM / SERINE/THREONINE-PROTEIN KINASE
Function / homology
Function and homology information


negative regulation of G0 to G1 transition / apoptotic process involved in development / histone H3T11 kinase activity / 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 / nucleus organization / negative regulation of gene expression, epigenetic ...negative regulation of G0 to G1 transition / apoptotic process involved in development / histone H3T11 kinase activity / 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 / nucleus organization / negative regulation of gene expression, epigenetic / Transcriptional Regulation by E2F6 / mitotic G2 DNA damage checkpoint signaling / 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 / DNA damage checkpoint signaling / regulation of signal transduction by p53 class mediator / replication fork / condensed nuclear chromosome / Ubiquitin-Mediated Degradation of Phosphorylated Cdc25A / TP53 Regulates Transcription of DNA Repair Genes / cellular response to mechanical stimulus / Signaling by SCF-KIT / G2/M DNA damage checkpoint / 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 / protein phosphorylation / non-specific serine/threonine protein kinase / protein kinase activity / chromatin remodeling / protein domain specific binding / protein serine kinase activity / DNA repair / intracellular membrane-bounded organelle / protein serine/threonine kinase activity / apoptotic process / DNA damage response / centrosome / chromatin / protein-containing complex / extracellular space / nucleoplasm / ATP binding / nucleus / cytoplasm / cytosol
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-DF1 / Serine/threonine-protein kinase Chk1
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.8 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 9, 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
Remark 700 SHEET THE SHEET STRUCTURE OF THIS MOLECULE IS BIFURCATED. IN ORDER TO REPRESENT THIS FEATURE IN ... SHEET THE SHEET STRUCTURE OF THIS MOLECULE IS BIFURCATED. IN ORDER TO REPRESENT THIS FEATURE IN THE SHEET RECORDS BELOW, TWO SHEETS ARE DEFINED.

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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)34,4932
Polymers34,1481
Non-polymers3441
Water2,468137
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
Unit cell
Length a, b, c (Å)44.907, 65.692, 54.429
Angle α, β, γ (deg.)90.00, 101.81, 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-DF1 / (2R)-1-[(5,6-DIPHENYL-7H-PYRROLO[2,3-D]PYRIMIDIN-4-YL)AMINO]PROPAN-2-OL


Mass: 344.410 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H20N4O
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 137 / Source method: isolated from a natural source / Formula: H2O
Compound detailsFUNCTION: PARTICIPATES IN THE ARREST OF THE CELL CYCLE WHEN THE DNA IS DAMAGED OR WHEN UNLIGATED ...FUNCTION: PARTICIPATES IN THE ARREST OF THE CELL CYCLE WHEN THE DNA IS DAMAGED OR WHEN UNLIGATED DNA IS PRESENT

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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: 56.9 %
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: 0.9792
DetectorType: MARRESEARCH / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9792 Å / Relative weight: 1
ReflectionResolution: 2.8→30 Å / Num. obs: 7714 / % possible obs: 97.9 % / Observed criterion σ(I): 2 / Redundancy: 3.2 % / Rmerge(I) obs: 0.13 / Net I/σ(I): 9.1
Reflection shellResolution: 2.8→2.9 Å / Redundancy: 3.2 % / Rmerge(I) obs: 0.51 / Mean I/σ(I) obs: 1 / % possible all: 98.9

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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: 2.8→65.94 Å / Cor.coef. Fo:Fc: 0.921 / Cor.coef. Fo:Fc free: 0.85 / SU B: 16.281 / SU ML: 0.327 / Cross valid method: THROUGHOUT / ESU R Free: 0.464 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.285 345 4.6 %RANDOM
Rwork0.203 ---
obs0.207 7204 97.8 %-
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: 45.58 Å2
Baniso -1Baniso -2Baniso -3
1--1.26 Å20 Å2-0.56 Å2
2---1.05 Å20 Å2
3---2.08 Å2
Refinement stepCycle: LAST / Resolution: 2.8→65.94 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2154 0 26 137 2317
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0212233
X-RAY DIFFRACTIONr_bond_other_d0.0020.022002
X-RAY DIFFRACTIONr_angle_refined_deg1.0521.953025
X-RAY DIFFRACTIONr_angle_other_deg0.78934668
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.775266
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_restr0.0650.2324
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.022451
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02432
X-RAY DIFFRACTIONr_nbd_refined0.1810.2498
X-RAY DIFFRACTIONr_nbd_other0.2040.22487
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other0.0820.21364
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.160.282
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1250.226
X-RAY DIFFRACTIONr_symmetry_vdw_other0.2080.271
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1470.29
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.7331.51337
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.35922157
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.0943896
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it2.1444.5868
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: 2.81→2.88 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rfree0.368 24
Rwork0.244 538

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