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- PDB-2xf0: Crystal structure of checkpoint kinase 1 (Chk1) in complex with i... -

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Basic information

Entry
Database: PDB / ID: 2xf0
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 / 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 / TP53 Regulates Transcription of DNA Repair Genes / Ubiquitin-Mediated Degradation of Phosphorylated Cdc25A / 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-4UB / Serine/threonine-protein kinase Chk1
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.4 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. / van Montfort, 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 1.0Jun 30, 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)33,5536
Polymers33,0431
Non-polymers5105
Water81145
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)44.759, 65.042, 53.039
Angle α, β, γ (deg.)90.00, 101.40, 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-4UB / 3-PHENYL-6-(1H-PYRAZOL-4-YL)IMIDAZO[1,2-A]PYRAZINE


Mass: 261.281 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H11N5
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


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


Mass: 18.015 Da / Num. of mol.: 45 / 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: 2.4 Å3/Da / Density % sol: 49.1 % / 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: Nov 17, 2005
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.4→30.7 Å / Num. obs: 10918 / % possible obs: 93 % / Observed criterion σ(I): 1.5 / Redundancy: 2.5 % / Biso Wilson estimate: 34.52 Å2 / Rmerge(I) obs: 0.1 / Net I/σ(I): 5.8
Reflection shellResolution: 2.4→2.53 Å / Redundancy: 2.4 % / Rmerge(I) obs: 0.53 / Mean I/σ(I) obs: 1.5 / % possible all: 96.3

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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: 2.4→27.746 Å / SU ML: 0.27 / σ(F): 1.34 / Phase error: 22.5 / Stereochemistry target values: MLHL
RfactorNum. reflection% reflection
Rfree0.2444 509 4.7 %
Rwork0.2026 --
obs0.2045 10899 92.63 %
Solvent computationShrinkage radii: 0.8 Å / VDW probe radii: 1 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 43.398 Å2 / ksol: 0.37 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1--10.466 Å20 Å2-4.4664 Å2
2--2.6886 Å2-0 Å2
3---7.7774 Å2
Refinement stepCycle: LAST / Resolution: 2.4→27.746 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2050 0 36 45 2131
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0072132
X-RAY DIFFRACTIONf_angle_d1.0022878
X-RAY DIFFRACTIONf_dihedral_angle_d15.978792
X-RAY DIFFRACTIONf_chiral_restr0.072310
X-RAY DIFFRACTIONf_plane_restr0.008366
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.4001-2.64140.28231200.25352671X-RAY DIFFRACTION96
2.6414-3.02320.26961500.22942621X-RAY DIFFRACTION95
3.0232-3.80740.26721320.19362587X-RAY DIFFRACTION92
3.8074-27.74780.20141070.17632511X-RAY DIFFRACTION88
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)
10.01280.0067-0.00360.0095-0.00040.0010.1096-0.00130.14320.00210.09540.06050.0572-0.0888-00.5487-0.1164-0.12980.58130.11790.39484.1524-5.8584-6.9225
20.2215-0.1496-0.02480.2847-0.01480.10710.39710.66380.2638-0.26210.1132-0.4001-0.05650.11390.00130.6583-0.0246-0.11790.4357-0.07820.29929.5512-4.9652-2.0831
30.3959-0.1098-0.25540.3556-0.07960.3051-0.13380.9914-0.0914-0.35140.0091-0.0749-0.0745-0.0927-0.04720.2139-0.0437-0.06920.4798-0.10460.16585.3336-1.04288.7201
40.61730.41160.11920.7367-0.03170.1495-0.19290.25420.0224-0.08850.0710.04870.01090.0299-0.02250.0347-0.0163-0.00830.079-0.00280.120910.93574.621519.1003
50.335-0.1119-0.0870.13060.04750.1384-0.2642-0.1573-0.5532-0.01170.0617-0.07160.0823-0.0073-0.06210.148-0.02890.03810.11680.08480.240810.4663-3.787730.808
65.42730.0305-1.29090.8828-0.51330.6550.3312-1.33160.59860.244-0.2482-0.2032-0.16060.41310.20120.1304-0.0236-0.00780.2696-0.03310.108120.83955.205134.3969
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1(CHAIN A AND RESID 4:9)
2X-RAY DIFFRACTION2(CHAIN A AND RESID 10:40)
3X-RAY DIFFRACTION3(CHAIN A AND RESID 41:97)
4X-RAY DIFFRACTION4(CHAIN A AND RESID 98:160)
5X-RAY DIFFRACTION5(CHAIN A AND RESID 161:214)
6X-RAY DIFFRACTION6(CHAIN A AND RESID 215:270)

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