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Basic information

Entry
Database: PDB / ID: 4bdf
TitleFragment-based screening identifies a new area for inhibitor binding to checkpoint kinase 2 (CHK2)
ComponentsSERINE/THREONINE-PROTEIN KINASE CHK2
KeywordsTRANSFERASE / INHIBITOR
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 / DNA damage response, signal transduction by p53 class mediator / Ubiquitin-Mediated Degradation of Phosphorylated Cdc25A / 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
5-METHYL-3-PHENYL-1H-PYRAZOLE / NITRATE ION / Serine/threonine-protein kinase Chk2
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.7 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.
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: SERINE/THREONINE-PROTEIN KINASE CHK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,4565
Polymers37,1121
Non-polymers3444
Water90150
1
A: SERINE/THREONINE-PROTEIN KINASE CHK2
hetero molecules

A: SERINE/THREONINE-PROTEIN KINASE CHK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)74,91210
Polymers74,2242
Non-polymers6898
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation6_555-x,-x+y,-z+2/31
Buried area3470 Å2
ΔGint-4.5 kcal/mol
Surface area28750 Å2
MethodPISA
Unit cell
Length a, b, c (Å)90.950, 90.950, 93.030
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 SERINE/THREONINE-PROTEIN KINASE CHK2 / CHK2 CHECKPOINT HOMOLOG / CDS1 HOMOLOG / HUCDS1 / HCDS1 / 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-H3R / 5-METHYL-3-PHENYL-1H-PYRAZOLE


Mass: 158.200 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H10N2
#3: Chemical ChemComp-NO3 / NITRATE ION


Mass: 62.005 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: NO3
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 50 / 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: 2.99 Å3/Da / Density % sol: 58.92 % / 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: I04 / Wavelength: 0.9728
DetectorType: ADSC CCD / Detector: CCD / Date: Dec 17, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9728 Å / Relative weight: 1
ReflectionResolution: 2.7→78.81 Å / Num. obs: 12578 / % possible obs: 99.8 % / Observed criterion σ(I): 1.5 / Redundancy: 3.5 % / Biso Wilson estimate: 85.71 Å2 / Rmerge(I) obs: 0.1 / Net I/σ(I): 8.7
Reflection shellResolution: 2.7→2.85 Å / Redundancy: 3.6 % / Rmerge(I) obs: 0.47 / Mean I/σ(I) obs: 3 / % possible all: 99.9

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Processing

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

2wtj


Resolution: 2.7→22.19 Å / Cor.coef. Fo:Fc: 0.9516 / Cor.coef. Fo:Fc free: 0.9329 / SU R Cruickshank DPI: 0.393 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.399 / SU Rfree Blow DPI: 0.265 / SU Rfree Cruickshank DPI: 0.267
Details: IDEAL-DIST CONTACT TERM CONTACT SETUP. ALL ATOMS HAVE CCP4 ATOM TYPE FROM LIBRARY
RfactorNum. reflection% reflectionSelection details
Rfree0.2334 608 4.86 %RANDOM
Rwork0.181 ---
obs0.1835 12518 99.5 %-
Displacement parametersBiso mean: 71.95 Å2
Baniso -1Baniso -2Baniso -3
1-0.9153 Å20 Å20 Å2
2--0.9153 Å20 Å2
3----1.8306 Å2
Refine analyzeLuzzati coordinate error obs: 0.365 Å
Refinement stepCycle: LAST / Resolution: 2.7→22.19 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2184 0 24 50 2258
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012249HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.163047HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d757SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes48HARMONIC2
X-RAY DIFFRACTIONt_gen_planes336HARMONIC5
X-RAY DIFFRACTIONt_it2249HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.42
X-RAY DIFFRACTIONt_other_torsion18.81
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion302SEMIHARMONIC5
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_contact2633SEMIHARMONIC4
LS refinement shellResolution: 2.7→2.96 Å / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.2642 148 5.03 %
Rwork0.2118 2794 -
all0.2144 2942 -
obs--99.5 %
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)
17.0578-3.9969-1.10582.03480.66980-0.6104-0.679-0.07520.53440.40340.01870.3152-0.17910.2070.31230.0959-0.00210.24810.05230.1396-39.414542.579412.271
23.5893-0.58770.41182.59460.1943.5405-0.03090.2984-0.1893-0.525-0.19270.346-0.1088-0.40040.22360.22350.0117-0.00290.1455-0.06980.1377-26.990528.44986.1579
31.3365-1.38990.79020.8051-0.29143.5981-0.27270.0536-0.4006-0.24140.2080.11110.22190.2050.06470.23840.0160.1380.20780.0450.3976-16.523921.127822.4613
44.4934-0.72570.31412.44730.07471.25350.0560.7136-0.276-0.8886-0.3035-0.25230.37160.53920.24750.4814-0.02660.06680.2976-0.12470.0613-17.189424.63540.77
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1CHAIN A AND RESID 210-301
2X-RAY DIFFRACTION2CHAIN A AND RESID 302-375
3X-RAY DIFFRACTION3CHAIN A AND RESID 376-445
4X-RAY DIFFRACTION4CHAIN A AND RESID 446-512

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