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- PDB-2xm8: Co-crystal structure of a small molecule inhibitor bound to the k... -

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Basic information

Entry
Database: PDB / ID: 2xm8
TitleCo-crystal structure of a small molecule inhibitor bound to the kinase domain of Chk2
ComponentsSERINE/THREONINE-PROTEIN KINASE CHK2
KeywordsTRANSFERASE / CANCER
Function / homology
Function and homology information


mitotic DNA damage checkpoint signaling / mitotic intra-S DNA damage checkpoint signaling / DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator / thymocyte apoptotic process / regulation of protein catabolic process / mitotic spindle assembly / replicative senescence / intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex / DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest ...mitotic DNA damage checkpoint signaling / mitotic intra-S DNA damage checkpoint signaling / DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator / thymocyte apoptotic process / regulation of protein catabolic process / mitotic spindle assembly / replicative senescence / intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex / DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest / signal transduction in response to DNA damage / DNA damage checkpoint signaling / regulation of signal transduction by p53 class mediator / Ubiquitin Mediated Degradation of Phosphorylated Cdc25A / Stabilization of p53 / protein catabolic process / cellular response to gamma radiation / G2/M DNA damage checkpoint / Regulation of TP53 Activity through Methylation / PML body / intrinsic apoptotic signaling pathway in response to DNA damage / G2/M transition of mitotic cell cycle / double-strand break repair / Regulation of TP53 Degradation / Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks / Regulation of TP53 Activity through Phosphorylation / protein autophosphorylation / protein stabilization / non-specific serine/threonine protein kinase / cell division / protein phosphorylation / 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 / identical protein binding / metal ion binding / nucleus / cytoplasm
Similarity search - Function
Forkhead associated domain / Forkhead-associated (FHA) domain profile. / FHA domain / Forkhead-associated (FHA) domain / SMAD/FHA domain superfamily / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; 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 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; 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-B4W / Serine/threonine-protein kinase Chk2
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.4 Å
AuthorsCaldwell, J.J. / Welsh, E.J. / Matijssen, C. / Anderson, V.E. / Antoni, L. / Boxall, K. / Urban, F. / Hayes, A. / Raynaud, F.I. / Rigoreau, L.J. ...Caldwell, J.J. / Welsh, E.J. / Matijssen, C. / Anderson, V.E. / Antoni, L. / Boxall, K. / Urban, F. / Hayes, A. / Raynaud, F.I. / Rigoreau, L.J. / Raynham, T. / Aherne, G.W. / Pearl, L.H. / Oliver, A.W. / Garrett, M.D. / Collins, I.
CitationJournal: J.Med.Chem. / Year: 2011
Title: Structure-Based Design of Potent and Selective 2-(Quinazolin-2-Yl)Phenol Inhibitors of Checkpoint Kinase 2.
Authors: Caldwell, J.J. / Welsh, E.J. / Matijssen, C. / Anderson, V.E. / Antoni, L. / Boxall, K. / Urban, F. / Hayes, A. / Raynaud, F.I. / Rigoreau, L.J. / Raynham, T. / Aherne, G.W. / Pearl, L.H. / ...Authors: Caldwell, J.J. / Welsh, E.J. / Matijssen, C. / Anderson, V.E. / Antoni, L. / Boxall, K. / Urban, F. / Hayes, A. / Raynaud, F.I. / Rigoreau, L.J. / Raynham, T. / Aherne, G.W. / Pearl, L.H. / Oliver, A.W. / Garrett, M.D. / Collins, I.
History
DepositionJul 26, 2010Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 12, 2011Provider: repository / Type: Initial release
Revision 1.1May 8, 2011Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Dec 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

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Assembly

Deposited unit
A: SERINE/THREONINE-PROTEIN KINASE CHK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,4182
Polymers37,1121
Non-polymers3061
Water362
1
A: SERINE/THREONINE-PROTEIN KINASE CHK2
hetero molecules

A: SERINE/THREONINE-PROTEIN KINASE CHK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)74,8364
Polymers74,2242
Non-polymers6132
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation6_554-x,-x+y,-z-1/31
Buried area1770 Å2
ΔGint-10.9 kcal/mol
Surface area26370 Å2
MethodPISA
Unit cell
Length a, b, c (Å)90.110, 90.110, 91.070
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 / CDS1 / 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): ROSETTA2 DE3(PLYSS)
References: UniProt: O96017, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-B4W / 2-{4-[(3S)-PYRROLIDIN-3-YLAMINO]QUINAZOLIN-2-YL}PHENOL


Mass: 306.362 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H18N4O
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 2 / 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: 3.5 Å3/Da / Density % sol: 64.89 % / Description: NONE
Crystal growDetails: 0.1 M HEPES PH 7.5, 0.2 M MAGNESIUM NITRATE, 8-16% (W/V) PEG 3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-2 / Wavelength: 0.933
DetectorType: ADSC CCD / Detector: CCD / Date: Dec 10, 2006 / Details: TOROIDAL MIRROR
RadiationMonochromator: DIAMOND (111), GE(220) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.933 Å / Relative weight: 1
ReflectionResolution: 3→39.33 Å / Num. obs: 6154 / % possible obs: 99.7 % / Observed criterion σ(I): 0 / Redundancy: 7.42 % / Biso Wilson estimate: 105.86 Å2 / Rmerge(I) obs: 0.08 / Net I/σ(I): 7.09
Reflection shellResolution: 3.4→3.58 Å / Redundancy: 7.69 % / Rmerge(I) obs: 0.5 / Mean I/σ(I) obs: 1.53 / % possible all: 99.9

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Processing

Software
NameVersionClassification
PHENIX(PHENIX.REFINE)refinement
iMOSFLMdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2CN5

2cn5


Resolution: 3.4→29.627 Å / SU ML: 0.47 / σ(F): 1.34 / Phase error: 33.92 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.3228 532 4.7 %
Rwork0.2628 --
obs0.2655 11348 99.69 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 0 Å2 / ksol: 0.306 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1--29.4313 Å2-0 Å20 Å2
2---29.4313 Å2-0 Å2
3---58.8625 Å2
Refinement stepCycle: LAST / Resolution: 3.4→29.627 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1843 0 23 2 1868
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0021906
X-RAY DIFFRACTIONf_angle_d0.5162614
X-RAY DIFFRACTIONf_dihedral_angle_d14.956583
X-RAY DIFFRACTIONf_chiral_restr0.036311
X-RAY DIFFRACTIONf_plane_restr0.001336
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.4001-3.74170.37951340.31862730X-RAY DIFFRACTION100
3.7417-4.28180.35911330.26232701X-RAY DIFFRACTION100
4.2818-5.38930.27921390.2592682X-RAY DIFFRACTION100
5.3893-29.62860.31461260.24772703X-RAY DIFFRACTION99

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