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Basic information

Entry
Database: PDB / ID: 2w7x
TitleCellular inhibition of checkpoint kinase 2 and potentiation of cytotoxic drugs by novel Chk2 inhibitor PV1019
ComponentsSERINE/THREONINE-PROTEIN KINASE CHK2
KeywordsTRANSFERASE / CO-CRYSTAL STRUCTURE / KINASE / NUCLEUS / MAGNESIUM / CELL CYCLE / ATP-BINDING / LI-FRAUMENI SYNDROME / SERINE/THREONINE-PROTEIN KINASE / DISEASE MUTATION / NUCLEOTIDE-BINDING / POTENTIATION / METAL-BINDING / PROTO-ONCOGENE / PHOSPHOPROTEIN / CHK2 INHIBITOR
Function / homology
Function and homology information


mitotic DNA damage checkpoint signaling / regulation of autophagosome assembly / positive regulation of autophagosome assembly / mitotic intra-S DNA damage checkpoint signaling / regulation of protein catabolic process / cellular response to stress / response to starvation / replicative senescence / mitotic spindle assembly / Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex ...mitotic DNA damage checkpoint signaling / regulation of autophagosome assembly / positive regulation of autophagosome assembly / mitotic intra-S DNA damage checkpoint signaling / regulation of protein catabolic process / cellular response to stress / response to starvation / replicative senescence / mitotic spindle assembly / Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex / DNA damage checkpoint signaling / signal transduction in response to DNA damage / regulation of signal transduction by p53 class mediator / DNA damage response, signal transduction by p53 class mediator / intrinsic apoptotic signaling pathway in response to DNA damage / G2/M transition of mitotic cell cycle / Stabilization of p53 / PML body / Regulation of TP53 Activity through Methylation / G2/M DNA damage checkpoint / protein catabolic process / Ubiquitin-Mediated Degradation of Phosphorylated Cdc25A / double-strand break repair / Regulation of TP53 Degradation / protein autophosphorylation / Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks / response to oxidative stress / Regulation of TP53 Activity through Phosphorylation / protein phosphorylation / non-specific serine/threonine protein kinase / protein stabilization / protein serine kinase activity / ubiquitin protein ligase binding / protein serine/threonine kinase activity / DNA damage response / regulation of DNA-templated transcription / positive regulation of DNA-templated transcription / protein kinase binding / protein homodimerization activity / nucleoplasm / ATP 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
Chem-D1A / NITRATE ION / Serine/threonine-protein kinase Chk2
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.07 Å
AuthorsJobson, A.G. / Lountos, G.T. / Lorenzi, P.L. / Llamas, J. / Connelly, J. / Tropea, J.E. / Onda, A. / Kondapaka, S. / Zhang, G. / Caplen, N.J. ...Jobson, A.G. / Lountos, G.T. / Lorenzi, P.L. / Llamas, J. / Connelly, J. / Tropea, J.E. / Onda, A. / Kondapaka, S. / Zhang, G. / Caplen, N.J. / Caredellina, J.H. / Monks, A. / Self, C. / Waugh, D.S. / Shoemaker, R.H. / Pommier, Y.
CitationJournal: J.Pharmacol.Exp.Ther. / Year: 2009
Title: Cellular Inhibition of Chk2 Kinase and Potentiation of Camptothecins and Radiation by the Novel Chk2 Inhibitor Pv1019.
Authors: Jobson, A.G. / Lountos, G.T. / Lorenzi, P.L. / Llamas, J. / Connelly, J. / Cerna, D. / Tropea, J.E. / Onda, A. / Zoppoli, G. / Kondapaka, S. / Zhang, G. / Caplen, N.J. / Cardellina, J.H. / ...Authors: Jobson, A.G. / Lountos, G.T. / Lorenzi, P.L. / Llamas, J. / Connelly, J. / Cerna, D. / Tropea, J.E. / Onda, A. / Zoppoli, G. / Kondapaka, S. / Zhang, G. / Caplen, N.J. / Cardellina, J.H. / Yoo, S.S. / Monks, A. / Self, C. / Waugh, D.S. / Shoemaker, R.H. / Pommier, Y.
History
DepositionJan 6, 2009Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 22, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Advisory / Refinement description / Version format compliance
Revision 1.2Dec 13, 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 / pdbx_struct_conn_angle / struct_conn / 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 / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _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)37,1526
Polymers36,5621
Non-polymers5905
Water3,477193
1
A: SERINE/THREONINE-PROTEIN KINASE CHK2
hetero molecules

A: SERINE/THREONINE-PROTEIN KINASE CHK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)74,30412
Polymers73,1242
Non-polymers1,18010
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation5_554x-y,-y,-z-2/31
Buried area3030 Å2
ΔGint-29.4 kcal/mol
Surface area35510 Å2
MethodPQS
Unit cell
Length a, b, c (Å)90.866, 90.866, 93.340
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number154
Space group name H-MP3221

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Components

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Protein , 1 types, 1 molecules A

#1: Protein SERINE/THREONINE-PROTEIN KINASE CHK2 / CHECKPOINT KINASE 2 / CDS1


Mass: 36562.238 Da / Num. of mol.: 1 / Fragment: CATALYTIC DOMAIN, RESIDUES 210-531
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: PDZ1927 / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21-CODONPLUS(DE3)-RIL
References: UniProt: O96017, non-specific serine/threonine protein kinase

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Non-polymers , 5 types, 198 molecules

#2: Chemical ChemComp-D1A / N-[4-[(E)-N-carbamimidamido-C-methyl-carbonimidoyl]phenyl]-7-nitro-1H-indole-2-carboxamide


Mass: 379.373 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H17N7O3
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-NO3 / NITRATE ION


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


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


Mass: 18.015 Da / Num. of mol.: 193 / Source method: isolated from a natural source / Formula: H2O

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Details

Nonpolymer details(Z)-N-(4-(1-(2-CARBAMIMIDOYLHYDRAZONO)ETHYL)PHENYL)-7-NITRO-1H-INDOL

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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: 3.1 Å3/Da / Density % sol: 60 % / Description: NONE
Crystal growpH: 7.8
Details: 0.1 M HEPES PH 7.8, 0.1 M MAGNESIUM NITRATE, 14% W/V PEG 3350, 16% V/V ETHYLENE GLYCOL

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-ID / Wavelength: 1
DetectorType: MARRESEARCH / Detector: CCD / Date: Jun 9, 2007
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.07→50 Å / Num. obs: 27547 / % possible obs: 99.6 % / Observed criterion σ(I): 2 / Redundancy: 7.3 % / Rmerge(I) obs: 0.05 / Net I/σ(I): 47.3
Reflection shellResolution: 2.07→2.14 Å / Redundancy: 7.4 % / Rmerge(I) obs: 0.45 / Mean I/σ(I) obs: 5.2 / % possible all: 99.4

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Processing

Software
NameVersionClassification
REFMAC5.4.0057refinement
HKL-3000data reduction
SCALEPACKdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2W0J

2w0j


Resolution: 2.07→50 Å / Cor.coef. Fo:Fc: 0.952 / Cor.coef. Fo:Fc free: 0.946 / SU B: 5.801 / SU ML: 0.101 / TLS residual ADP flag: LIKELY RESIDUAL / Cross valid method: THROUGHOUT / ESU R: 0.162 / ESU R Free: 0.144 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.22 1383 5 %RANDOM
Rwork0.193 ---
obs0.195 26152 99.5 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 29.85 Å2
Baniso -1Baniso -2Baniso -3
1--0.03 Å2-0.01 Å20 Å2
2---0.03 Å20 Å2
3---0.04 Å2
Refinement stepCycle: LAST / Resolution: 2.07→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2280 0 41 193 2514
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.0222371
X-RAY DIFFRACTIONr_bond_other_d0.0010.021635
X-RAY DIFFRACTIONr_angle_refined_deg1.462.0023198
X-RAY DIFFRACTIONr_angle_other_deg0.92934012
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.4225286
X-RAY DIFFRACTIONr_dihedral_angle_2_deg39.86124.84899
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.0215447
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.761510
X-RAY DIFFRACTIONr_chiral_restr0.090.2362
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0212556
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02452
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.8641.51427
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.57722310
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it2.3563944
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it3.8324.5886
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.07→2.12 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rfree0.309 101
Rwork0.202 1840
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)
15.23-3.06350.6931.9763-0.21520.29190.1050.4389-0.01320.031-0.13950.02430.18890.030.0345-0.03440.0074-0.01220.03410.0304-0.043756.338-12.865-11.898
22.9757-0.40140.29211.7966-0.41132.0777-0.0279-0.365-0.27440.0997-0.0446-0.00960.0650.13120.0725-0.018-0.02420.01590.00440.07-0.071638.139-8.943-5.937
30.7914-0.2433-0.0110.8939-1.00951.77360.0432-0.0422-0.11940.084-0.0710.1483-0.1176-0.09320.0277-0.0424-0.01430.0233-0.054-0.01380.012425.815-4.658-21.391
4000000000000000000000000
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A210 - 300
2X-RAY DIFFRACTION2A301 - 374
3X-RAY DIFFRACTION3A375 - 448
4X-RAY DIFFRACTION4A449 - 510

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