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- PDB-1oit: Imidazopyridines: a potent and selective class of Cyclin-dependen... -

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Entry
Database: PDB / ID: 1oit
TitleImidazopyridines: a potent and selective class of Cyclin-dependent Kinase inhibitors identified through Structure-based hybridisation
ComponentsCELL DIVISION PROTEIN KINASE 2
KeywordsKINASE / PROTEIN KINASE
Function / homology
Function and homology information


cyclin A1-CDK2 complex / cyclin E2-CDK2 complex / cyclin E1-CDK2 complex / cyclin A2-CDK2 complex / positive regulation of DNA-templated DNA replication initiation / cyclin-dependent protein kinase activity / G2 Phase / Y chromosome / Phosphorylation of proteins involved in G1/S transition by active Cyclin E:Cdk2 complexes / positive regulation of heterochromatin formation ...cyclin A1-CDK2 complex / cyclin E2-CDK2 complex / cyclin E1-CDK2 complex / cyclin A2-CDK2 complex / positive regulation of DNA-templated DNA replication initiation / cyclin-dependent protein kinase activity / G2 Phase / Y chromosome / Phosphorylation of proteins involved in G1/S transition by active Cyclin E:Cdk2 complexes / positive regulation of heterochromatin formation / p53-Dependent G1 DNA Damage Response / X chromosome / PTK6 Regulates Cell Cycle / regulation of anaphase-promoting complex-dependent catabolic process / Defective binding of RB1 mutants to E2F1,(E2F2, E2F3) / centriole replication / Regulation of APC/C activators between G1/S and early anaphase / telomere maintenance in response to DNA damage / centrosome duplication / Telomere Extension By Telomerase / G0 and Early G1 / Activation of the pre-replicative complex / cyclin-dependent kinase / cyclin-dependent protein serine/threonine kinase activity / TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest / Regulation of MITF-M-dependent genes involved in cell cycle and proliferation / Activation of ATR in response to replication stress / Cajal body / Cyclin A/B1/B2 associated events during G2/M transition / Cyclin E associated events during G1/S transition / Cyclin A:Cdk2-associated events at S phase entry / cyclin-dependent protein kinase holoenzyme complex / condensed chromosome / mitotic G1 DNA damage checkpoint signaling / regulation of G2/M transition of mitotic cell cycle / regulation of mitotic cell cycle / cellular response to nitric oxide / post-translational protein modification / cyclin binding / positive regulation of DNA replication / male germ cell nucleus / meiotic cell cycle / potassium ion transport / DNA Damage/Telomere Stress Induced Senescence / CDK-mediated phosphorylation and removal of Cdc6 / Meiotic recombination / SCF(Skp2)-mediated degradation of p27/p21 / G1/S transition of mitotic cell cycle / Orc1 removal from chromatin / Transcriptional regulation of granulopoiesis / G2/M transition of mitotic cell cycle / Cyclin D associated events in G1 / cellular senescence / Regulation of TP53 Degradation / nuclear envelope / Factors involved in megakaryocyte development and platelet production / Processing of DNA double-strand break ends / Senescence-Associated Secretory Phenotype (SASP) / regulation of gene expression / peptidyl-serine phosphorylation / Regulation of TP53 Activity through Phosphorylation / transcription regulator complex / Ras protein signal transduction / DNA replication / chromosome, telomeric region / endosome / chromatin remodeling / protein domain specific binding / protein phosphorylation / cell division / protein serine/threonine kinase activity / protein serine kinase activity / DNA repair / DNA-templated transcription / centrosome / positive regulation of cell population proliferation / positive regulation of DNA-templated transcription / negative regulation of transcription by RNA polymerase II / magnesium ion binding / signal transduction / nucleoplasm / ATP binding / nucleus / cytosol / cytoplasm
Similarity search - Function
: / Phosphorylase Kinase; domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site ...: / Phosphorylase Kinase; domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / 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-HDT / Cyclin-dependent kinase 2
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.6 Å
AuthorsBeattie, J.F. / Breault, G.A. / Byth, K.F. / Culshaw, J.D. / Ellston, R.P.A. / Green, S. / Minshull, C.A. / Norman, R.A. / Pauptit, R.A. / Thomas, A.P. / Jewsbury, P.J.
Citation
Journal: Bioorg.Med.Chem.Lett. / Year: 2003
Title: Imidazo[1,2-A]Pyridines: A Potent and Selective Class of Cyclin-Dependent Kinase Inhibitors Identified Through Structure-Based Hybridisation
Authors: Anderson, M. / Beattie, J.F. / Breault, G.A. / Breed, J. / Byth, K.F. / Culshaw, J.D. / Ellston, R.P.A. / Green, S. / Minshull, C.A. / Norman, R.A. / Pauptit, R.A. / Stanway, J. / Thomas, A.P. / Jewsbury, P.J.
#1: Journal: J.Med.Chem. / Year: 1996
Title: High-Resolution Crystal Structures of Human Cyclin-Dependent Kinase 2 with and without ATP: Bound Waters and Natural Ligand as a Guide for Inhibitor Design
Authors: Schulze-Gahmen, U. / De Bondt, H. / Kim, S.-H.
History
DepositionJun 24, 2003Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 4, 2003Provider: repository / Type: Initial release
Revision 1.1May 8, 2011Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3May 8, 2024Group: Data collection / Database references / Other
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf
Revision 1.4Nov 13, 2024Group: Structure summary / Category: pdbx_entry_details

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: CELL DIVISION PROTEIN KINASE 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,3852
Polymers34,0191
Non-polymers3661
Water3,495194
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
Unit cell
Length a, b, c (Å)53.466, 72.239, 72.227
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein CELL DIVISION PROTEIN KINASE 2 / P33 PROTEIN KINASE


Mass: 34018.527 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: SPODOPTERA FRUGIPERDA (fall armyworm) / Strain (production host): SF9 / References: UniProt: P24941, EC: 2.7.1.37
#2: Chemical ChemComp-HDT / 4-[(4-IMIDAZO[1,2-A]PYRIDIN-3-YLPYRIMIDIN-2-YL)AMINO]BENZENESULFONAMIDE


Mass: 366.397 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H14N6O2S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 194 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationN

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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: 2.24 Å3/Da / Density % sol: 40 %
Crystal growpH: 7
Details: PROTEIN AT 10MG/ML WELL BUFFER CONTAINING 17.5% PEG3350, 200MM HEPES, PH7.0, 100MM AMMONIUM ACETATE, pH 7.00
Crystal grow
*PLUS
Temperature: 20 ℃ / pH: 7.4 / Method: vapor diffusion, sitting drop / Details: Lawrie, A.M., (1997) Nature Struct. Biol., 4, 796.
Components of the solutions
*PLUS
IDConc.Common nameCrystal-IDSol-IDChemical formulaDetails
110 mg/mlprotein1drop
215 mM1dropNaCl
310 mMHEPES1droppH7.4
450 mM1reservoirNH4Ac
510 %PEG40001reservoir
60.1 MHEPES1reservoirpH7.4

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SRS / Beamline: PX9.6 / Wavelength: 0.87
DetectorType: ADSC CCD / Detector: CCD / Date: Sep 15, 1999
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.87 Å / Relative weight: 1
ReflectionResolution: 1.6→51.3 Å / Num. obs: 33885 / % possible obs: 80.7 % / Redundancy: 2.1 % / Rmerge(I) obs: 0.045 / Net I/σ(I): 17.8
Reflection shellResolution: 1.6→1.69 Å / Redundancy: 1.6 % / Rmerge(I) obs: 0.578 / Mean I/σ(I) obs: 1.5 / % possible all: 38.8
Reflection
*PLUS
Highest resolution: 1.6 Å / Num. measured all: 179548 / Rmerge(I) obs: 0.035

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Processing

Software
NameClassification
REFMACrefinement
MOSFLMdata reduction
SCALAdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.6→51.3 Å / SU B: 3.01 / SU ML: 0.097 / Cross valid method: THROUGHOUT / ESU R: 0.142 / ESU R Free: 0.122 / Details: TLS REFINEMENT CARRIED OUT
RfactorNum. reflection% reflectionSelection details
Rfree0.24013 1490 5 %RANDOM
Rwork0.2259 ---
obs0.22661 28566 79.93 %-
Displacement parametersBiso mean: 17.73 Å2
Baniso -1Baniso -2Baniso -3
1-0.09 Å20 Å20 Å2
2---1.52 Å20 Å2
3---1.43 Å2
Refinement stepCycle: LAST / Resolution: 1.6→51.3 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2196 0 26 194 2416
Refinement
*PLUS
% reflection Rfree: 5 % / Rfactor Rfree: 0.255 / Rfactor Rwork: 0.263
Solvent computation
*PLUS
Displacement parameters
*PLUS

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