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- PDB-2xez: Crystal structure of checkpoint kinase 1 (Chk1) in complex with i... -

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Basic information

Entry
Database: PDB / ID: 2xez
TitleCrystal structure of checkpoint kinase 1 (Chk1) in complex with inhibitors
ComponentsSERINE/THREONINE-PROTEIN KINASE CHK1
KeywordsTRANSFERASE / DNA REPAIR / CELL CYCLE
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 / Transcriptional Regulation by E2F6 / mitotic G2 DNA damage checkpoint signaling / Presynaptic phase of homologous DNA pairing and strand exchange / replicative senescence / signal transduction in response to DNA damage / positive regulation of cell cycle / Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex / Activation of ATR in response to replication stress / regulation of signal transduction by p53 class mediator / DNA damage checkpoint signaling / 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 / 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-XEZ / Serine/threonine-protein kinase Chk1
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.25 Å
AuthorsMatthews, T.P. / McHardy, T. / Klair, S. / Boxall, K. / Fisher, M. / Cherry, M. / Allen, C.E. / Addison, G.J. / Ellard, J. / Aherne, G.W. ...Matthews, T.P. / McHardy, T. / Klair, S. / Boxall, K. / Fisher, M. / Cherry, M. / Allen, C.E. / Addison, G.J. / Ellard, J. / Aherne, G.W. / Westwood, I.M. / vanMontfort, R. / Garrett, M.D. / Reader, J.C. / Collins, I.
Citation
Journal: Bioorg.Med.Chem.Lett. / Year: 2010
Title: Design and Evaluation of 3,6-Di(Hetero)Aryl Imidazo[1,2-A]Pyrazines as Inhibitors of Checkpoint and Other Kinases.
Authors: Matthews, T.P. / Mchardy, T. / Klair, S. / Boxall, K. / Fisher, M. / Cherry, M. / Allen, C.E. / Addison, G.J. / Ellard, J. / Aherne, G.W. / Westwood, I.M. / Montfort, R.V. / Garrett, M.D. / ...Authors: Matthews, T.P. / Mchardy, T. / Klair, S. / Boxall, K. / Fisher, M. / Cherry, M. / Allen, C.E. / Addison, G.J. / Ellard, J. / Aherne, G.W. / Westwood, I.M. / Montfort, R.V. / Garrett, M.D. / Reader, J.C. / Collins, I.
#1: Journal: J.Med.Chem. / Year: 2009
Title: Identification of Inhibitors of Checkpoint Kinase 1 Through Template Screening.
Authors: Matthews, T.P. / Klair, S. / Burns, S. / Boxall, K. / Cherry, M. / Fisher, M. / Westwood, I.M. / Walton, M.I. / Mchardy, T. / Cheung, K.J. / Van Montfort, R. / Williams, D. / Aherne, G.W. / ...Authors: Matthews, T.P. / Klair, S. / Burns, S. / Boxall, K. / Cherry, M. / Fisher, M. / Westwood, I.M. / Walton, M.I. / Mchardy, T. / Cheung, K.J. / Van Montfort, R. / Williams, D. / Aherne, G.W. / Garrett, M.D. / Reader, J. / Collins, I.
History
DepositionMay 19, 2010Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 7, 2010Provider: repository / Type: Initial release
Revision 1.1May 8, 2011Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Jun 28, 2017Group: Data collection / Category: diffrn_source / Item: _diffrn_source.type
Revision 1.4Dec 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)33,6678
Polymers33,0431
Non-polymers6247
Water1,20767
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)44.840, 65.600, 57.450
Angle α, β, γ (deg.)90.00, 95.11, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein SERINE/THREONINE-PROTEIN KINASE CHK1 / CHECKPOINT KINASE 1 / CHEK1 / CHK1


Mass: 33042.988 Da / Num. of mol.: 1 / Fragment: KINASE DOMAIN, RESIDUES 1-289
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-XEZ / 6-(1H-PYRAZOL-3-YL)-3-(1H-PYRAZOL-4-YL)IMIDAZO[1,2-A]PYRAZINE


Mass: 251.247 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C12H9N7
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


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


Mass: 18.015 Da / Num. of mol.: 67 / Source method: isolated from a natural source / Formula: H2O
Nonpolymer details3-(1H-PYRAZOL-3-YL)-6-(1H-PYRAZOL-4-YL)IMIDAZO[1, 2-A]PYRAZINE (XEZ): PYRAZOL-3-YL MAY BE MODELLED ...3-(1H-PYRAZOL-3-YL)-6-(1H-PYRAZOL-4-YL)IMIDAZO[1, 2-A]PYRAZINE (XEZ): PYRAZOL-3-YL MAY BE MODELLED IN EITHER ORIENTATION, CO-PLANAR WITH IMIDAZOPYRAZINE RING.

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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: 2.7 Å3/Da / Density % sol: 54.3 % / Description: NONE
Crystal growDetails: DL-MALIC ACID/PEG3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.5418
DetectorType: RIGAKU CCD / Detector: CCD / Date: May 11, 2006
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.25→44.7 Å / Num. obs: 15276 / % possible obs: 96.4 % / Observed criterion σ(I): 1.5 / Redundancy: 2.6 % / Biso Wilson estimate: 37.53 Å2 / Rmerge(I) obs: 0.08 / Net I/σ(I): 8.6
Reflection shellResolution: 2.25→2.37 Å / Redundancy: 2.6 % / Rmerge(I) obs: 0.48 / Mean I/σ(I) obs: 1.6 / % possible all: 98.6

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Processing

Software
NameVersionClassification
PHENIX(PHENIX.REFINE)refinement
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2WMW

2wmw


Resolution: 2.25→36.918 Å / SU ML: 0.35 / σ(F): 1.34 / Phase error: 22.52 / Stereochemistry target values: MLHL
Details: PYRAZOL-3-YL MOIETY CAN BE MODELED IN EITHER CO-PLANAR CONFORMATION.
RfactorNum. reflection% reflection
Rfree0.2375 736 4.8 %
Rwork0.2102 --
obs0.2114 15253 96.11 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 63.592 Å2 / ksol: 0.378 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1--9.5666 Å2-0 Å21.419 Å2
2---2.2871 Å2-0 Å2
3---11.8537 Å2
Refinement stepCycle: LAST / Resolution: 2.25→36.918 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2039 0 43 67 2149
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.012125
X-RAY DIFFRACTIONf_angle_d1.0812863
X-RAY DIFFRACTIONf_dihedral_angle_d17.717791
X-RAY DIFFRACTIONf_chiral_restr0.095307
X-RAY DIFFRACTIONf_plane_restr0.008364
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.2501-2.42380.27371550.27512938X-RAY DIFFRACTION98
2.4238-2.66760.2851350.24922955X-RAY DIFFRACTION98
2.6676-3.05350.2751710.21372904X-RAY DIFFRACTION97
3.0535-3.84640.19941540.18732881X-RAY DIFFRACTION96
3.8464-36.92290.21771210.18542839X-RAY DIFFRACTION92
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.4024-0.70840.30171.3143-0.71850.7680.14470.9882-0.0580.0388-0.4179-0.627-0.0595-0.1756-0.03030.7776-0.0888-0.02061.0378-0.12040.308511.0517-2.91810.1751
22.7036-1.1585-1.4852.8802-0.50542.0737-0.23221.2859-0.0224-0.94140.13950.230.1246-0.4719-0.00530.424-0.1022-0.06990.55530.01850.189813.16773.200314.3573
31.0305-0.28010.44561.11970.05060.4088-0.17910.63660.0075-0.43770.04010.14780.08510.0761-00.2711-0.0032-0.03520.32920.03040.23889.91615.340220.8081
40.3521-0.10780.02360.707-0.59050.618-0.13550.0517-0.2115-0.08450.03930.389-0.1547-0.1333-00.2142-0.01420.01660.22510.03020.37986.5962-1.171934.1704
50.67690.1684-0.32030.78970.63930.8308-0.1468-0.7386-0.23850.4252-0.1104-0.55690.00080.3639-0.00040.25880.0202-0.03040.36720.12710.364825.57190.855736.6447
63.6687-0.593-0.65220.3523-0.14610.60580.3592-0.49120.98030.3639-0.0086-0.1525-0.20950.0880.03230.2725-0.00580.06120.2216-0.00960.309818.046913.523734.521
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1(CHAIN A AND RESID 7:42)
2X-RAY DIFFRACTION2(CHAIN A AND RESID 51:113)
3X-RAY DIFFRACTION3(CHAIN A AND RESID 114:158)
4X-RAY DIFFRACTION4(CHAIN A AND RESID 159:192)
5X-RAY DIFFRACTION5(CHAIN A AND RESID 193:246)
6X-RAY DIFFRACTION6(CHAIN A AND RESID 247:269)

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