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Basic information

Entry
Database: PDB / ID: 4bdj
TitleFragment-based screening identifies a new area for inhibitor binding to checkpoint kinase 2 (CHK2)
ComponentsCHECKPOINT KINASE 2
KeywordsTRANSFERASE
Function / homology
Function and homology information


positive regulation of anoikis / mitotic DNA damage checkpoint signaling / cellular response to bisphenol A / regulation of autophagosome assembly / mitotic intra-S DNA damage checkpoint signaling / response to glycoside / thymocyte apoptotic process / cellular response to stress / regulation of protein catabolic process / negative regulation of DNA damage checkpoint ...positive regulation of anoikis / mitotic DNA damage checkpoint signaling / cellular response to bisphenol A / regulation of autophagosome assembly / mitotic intra-S DNA damage checkpoint signaling / response to glycoside / thymocyte apoptotic process / cellular response to stress / regulation of protein catabolic process / negative regulation of DNA damage checkpoint / replicative senescence / signal transduction in response to DNA damage / intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / mitotic spindle assembly / Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex / DNA damage checkpoint signaling / regulation of signal transduction by p53 class mediator / Ubiquitin-Mediated Degradation of Phosphorylated Cdc25A / DNA damage response, signal transduction by p53 class mediator / Stabilization of p53 / protein catabolic process / cellular response to gamma radiation / PML body / G2/M DNA damage checkpoint / Regulation of TP53 Activity through Methylation / G2/M transition of mitotic cell cycle / cellular response to xenobiotic stimulus / intrinsic apoptotic signaling pathway in response to DNA damage / Regulation of TP53 Degradation / double-strand break repair / Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks / protein autophosphorylation / Regulation of TP53 Activity through Phosphorylation / protein phosphorylation / non-specific serine/threonine protein kinase / protein stabilization / cell division / protein serine kinase activity / protein serine/threonine kinase activity / DNA damage response / ubiquitin protein ligase binding / regulation of DNA-templated transcription / protein kinase binding / positive regulation of DNA-templated transcription / Golgi apparatus / protein homodimerization activity / nucleoplasm / ATP binding / metal ion binding / identical protein binding / nucleus / cytoplasm
Similarity search - Function
Forkhead associated domain / Forkhead-associated (FHA) domain profile. / FHA domain / Forkhead-associated (FHA) domain / SMAD/FHA domain superfamily / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Serine/threonine-protein kinase, active site ...Forkhead associated domain / Forkhead-associated (FHA) domain profile. / FHA domain / Forkhead-associated (FHA) domain / SMAD/FHA domain superfamily / 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 domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
NITRATE ION / Chem-Z2M / Serine/threonine-protein kinase Chk2
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.01 Å
AuthorsSilva-Santisteban, M.C. / Westwood, I.M. / Boxall, K. / Brown, N. / Peacock, S. / McAndrew, C. / Barrie, E. / Richards, M. / Mirza, A. / Oliver, A.W. ...Silva-Santisteban, M.C. / Westwood, I.M. / Boxall, K. / Brown, N. / Peacock, S. / McAndrew, C. / Barrie, E. / Richards, M. / Mirza, A. / Oliver, A.W. / Burke, R. / Hoelder, S. / Jones, K. / Aherne, G.W. / Blagg, J. / Collins, I. / Garrett, M.D. / van Montfort, R.L.M.
CitationJournal: Plos One / Year: 2013
Title: Fragment-Based Screening Maps Inhibitor Interactions in the ATP-Binding Site of Checkpoint Kinase 2.
Authors: Silva-Santisteban, M.C. / Westwood, I.M. / Boxall, K. / Brown, N. / Peacock, S. / Mcandrew, C. / Barrie, E. / Richards, M. / Mirza, A. / Oliver, A.W. / Burke, R. / Hoelder, S. / Jones, K. / ...Authors: Silva-Santisteban, M.C. / Westwood, I.M. / Boxall, K. / Brown, N. / Peacock, S. / Mcandrew, C. / Barrie, E. / Richards, M. / Mirza, A. / Oliver, A.W. / Burke, R. / Hoelder, S. / Jones, K. / Aherne, G.W. / Blagg, J. / Collins, I. / Garrett, M.D. / Van Montfort, R.L.M.
History
DepositionOct 5, 2012Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 26, 2013Provider: repository / Type: Initial release
Revision 1.1Dec 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: CHECKPOINT KINASE 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,3993
Polymers37,1121
Non-polymers2872
Water724
1
A: CHECKPOINT KINASE 2
hetero molecules

A: CHECKPOINT KINASE 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)74,7986
Polymers74,2242
Non-polymers5754
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation5_555x-y,-y,-z+1/31
Buried area2870 Å2
ΔGint-12.8 kcal/mol
Surface area27860 Å2
MethodPISA
Unit cell
Length a, b, c (Å)90.930, 90.930, 92.130
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number154
Space group name H-MP3221

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Components

#1: Protein CHECKPOINT KINASE 2


Mass: 37111.844 Da / Num. of mol.: 1 / Fragment: KINASE DOMAIN, RESIDUES 210-531
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: PTHREE-E / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21(DE3) / Variant (production host): ROSETTA2 PLYSS
References: UniProt: O96017, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-Z2M / 3-cyclopropyl-4-(furan-2-yl)-1H-pyrazolo[3,4-b]pyridine


Mass: 225.246 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C13H11N3O
#3: Chemical ChemComp-NO3 / NITRATE ION


Mass: 62.005 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: NO3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 4 / 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: 3.62 Å3/Da / Density % sol: 65.79 % / Description: NONE
Crystal growDetails: 0.1 M HEPES 7.5, 0.2 M MG(NO3)2, 10% (V/V) ETHYLENE GLYCOL, 1 MM TCEP AND 8-14% (W/V) PEG 3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I24 / Wavelength: 0.96861
DetectorType: DECTRIS PILATUS / Detector: PIXEL / Date: Jul 29, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.96861 Å / Relative weight: 1
ReflectionResolution: 3.01→36.21 Å / Num. obs: 9073 / % possible obs: 99.9 % / Observed criterion σ(I): 1.5 / Redundancy: 8.5 % / Biso Wilson estimate: 95.83 Å2 / Rmerge(I) obs: 0.06 / Net I/σ(I): 22.9
Reflection shellResolution: 3.01→3.09 Å / Redundancy: 8.4 % / Rmerge(I) obs: 0.67 / Mean I/σ(I) obs: 3.4 / % possible all: 99.9

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Processing

Software
NameVersionClassification
BUSTER2.11.2refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2WTJ

2wtj


Resolution: 3.01→36.21 Å / Cor.coef. Fo:Fc: 0.9492 / Cor.coef. Fo:Fc free: 0.9265 / SU R Cruickshank DPI: 1.258 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 1.251 / SU Rfree Blow DPI: 0.31 / SU Rfree Cruickshank DPI: 0.315
RfactorNum. reflection% reflectionSelection details
Rfree0.2146 434 4.79 %RANDOM
Rwork0.1771 ---
obs0.179 9055 99.93 %-
Displacement parametersBiso mean: 95.14 Å2
Baniso -1Baniso -2Baniso -3
1-6.8204 Å20 Å20 Å2
2--6.8204 Å20 Å2
3----13.6408 Å2
Refine analyzeLuzzati coordinate error obs: 0.553 Å
Refinement stepCycle: LAST / Resolution: 3.01→36.21 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2141 0 21 4 2166
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012206HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.143001HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d729SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes43HARMONIC2
X-RAY DIFFRACTIONt_gen_planes339HARMONIC5
X-RAY DIFFRACTIONt_it2206HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.41
X-RAY DIFFRACTIONt_other_torsion19.4
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion303SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact2628SEMIHARMONIC4
LS refinement shellResolution: 3.01→3.37 Å / Total num. of bins used: 5
RfactorNum. reflection% reflection
Rfree0.2529 121 4.8 %
Rwork0.2066 2400 -
all0.2088 2521 -
obs--99.93 %
Refinement TLS params.Method: refined / Origin x: 38.1205 Å / Origin y: 7.2639 Å / Origin z: -5.2136 Å
111213212223313233
T-0.2629 Å20.0661 Å2-0.0626 Å2--0.2814 Å2-0.0371 Å2---0.2797 Å2
L3.3884 °21.3403 °2-1.7246 °2-1.5911 °2-0.1152 °2--2.1609 °2
S0.1108 Å °0.2349 Å °0.268 Å °-0.3275 Å °-0.2201 Å °0.163 Å °-0.1713 Å °0.017 Å °0.1093 Å °
Refinement TLS groupSelection details: CHAIN A

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