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- PDB-4bdk: Fragment-based screening identifies a new area for inhibitor bind... -

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Basic information

Entry
Database: PDB / ID: 4bdk
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 / 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 / ubiquitin protein ligase binding / DNA damage response / 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-RQQ / Serine/threonine-protein kinase Chk2
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 3.3 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 1.1Jul 5, 2017Group: Data collection / Category: diffrn_source / Item: _diffrn_source.type
Revision 1.2Dec 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)37,6536
Polymers37,1121
Non-polymers5425
Water50428
1
A: CHECKPOINT KINASE 2
hetero molecules

A: CHECKPOINT KINASE 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)75,30712
Polymers74,2242
Non-polymers1,08310
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation6_555-x,-x+y,-z+2/31
Buried area4170 Å2
ΔGint5.7 kcal/mol
Surface area27900 Å2
MethodPISA
Unit cell
Length a, b, c (Å)91.010, 91.010, 92.840
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-RQQ / N-[(4-methoxyphenyl)methyl]quinoxaline-6-carboxamide


Mass: 293.320 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H15N3O2
#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.: 3 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 28 / 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: 3.54 Å3/Da / Density % sol: 64.99 % / 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: ROTATING ANODE / Type: BRUKER AXS MICROSTAR / Wavelength: 1.54189
DetectorType: Bruker Platinum 135 / Detector: CCD / Date: Jul 19, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54189 Å / Relative weight: 1
ReflectionResolution: 3.3→45.5 Å / Num. obs: 6975 / % possible obs: 99.5 % / Observed criterion σ(I): 1.5 / Redundancy: 8.3 % / Biso Wilson estimate: 50.76 Å2 / Rmerge(I) obs: 0.11 / Net I/σ(I): 8.7
Reflection shellResolution: 3.3→3.4 Å / Redundancy: 7.1 % / Rmerge(I) obs: 0.29 / Mean I/σ(I) obs: 3.4 / % possible all: 100

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Processing

Software
NameVersionClassification
BUSTER2.11.2refinement
PROTEUM2data reduction
PROTEUM2data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2WTJ

2wtj


Resolution: 3.3→45.5 Å / Cor.coef. Fo:Fc: 0.9054 / Cor.coef. Fo:Fc free: 0.8416 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.432
RfactorNum. reflection% reflectionSelection details
Rfree0.2329 332 4.77 %RANDOM
Rwork0.1682 ---
obs0.1711 6957 99.58 %-
Displacement parametersBiso mean: 49.58 Å2
Baniso -1Baniso -2Baniso -3
1-8.4297 Å20 Å20 Å2
2--8.4297 Å20 Å2
3----16.8593 Å2
Refinement stepCycle: LAST / Resolution: 3.3→45.5 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2172 0 38 28 2238
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012251HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.193050HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d751SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes44HARMONIC2
X-RAY DIFFRACTIONt_gen_planes348HARMONIC5
X-RAY DIFFRACTIONt_it2251HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.43
X-RAY DIFFRACTIONt_other_torsion19.02
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_contact2707SEMIHARMONIC4
LS refinement shellResolution: 3.3→3.69 Å / Total num. of bins used: 5
RfactorNum. reflection% reflection
Rfree0.2443 102 5.29 %
Rwork0.1762 1825 -
all0.1797 1927 -
obs--99.58 %
Refinement TLS params.Method: refined / Origin x: 25.2438 Å / Origin y: -29.5361 Å / Origin z: 10.2214 Å
111213212223313233
T0.0134 Å2-0.0144 Å2-0.0511 Å2--0.0912 Å20.0433 Å2---0.225 Å2
L3.058 °2-1.2929 °2-0.9421 °2-1.3397 °21.3045 °2--1.5943 °2
S-0.1297 Å °0.145 Å °0.2851 Å °-0.2599 Å °0.0766 Å °-0.1904 Å °0.0045 Å °0.1995 Å °0.0531 Å °
Refinement TLS groupSelection details: CHAIN A

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