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

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Basic information

Entry
Database: PDB / ID: 1oir
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 / G2 Phase / cyclin-dependent protein kinase activity / 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 / G2 Phase / cyclin-dependent protein kinase activity / 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 / centrosome duplication / Telomere Extension By Telomerase / G0 and Early G1 / Activation of the pre-replicative complex / cyclin-dependent protein kinase holoenzyme complex / cellular response to nitric oxide / Cajal body / cyclin-dependent kinase / cyclin-dependent protein serine/threonine kinase activity / Activation of ATR in response to replication stress / TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest / Cyclin E associated events during G1/S transition / Cyclin A/B1/B2 associated events during G2/M transition / Cyclin A:Cdk2-associated events at S phase entry / condensed chromosome / mitotic G1 DNA damage checkpoint signaling / regulation of G2/M transition of mitotic cell cycle / cyclin binding / post-translational protein modification / meiotic cell cycle / male germ cell nucleus / response to organic substance / G1/S transition of mitotic cell cycle / potassium ion transport / DNA Damage/Telomere Stress Induced Senescence / CDK-mediated phosphorylation and removal of Cdc6 / SCF(Skp2)-mediated degradation of p27/p21 / Meiotic recombination / Orc1 removal from chromatin / Transcriptional regulation of granulopoiesis / Cyclin D associated events in G1 / G2/M transition of mitotic cell cycle / 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 / Ras protein signal transduction / Regulation of TP53 Activity through Phosphorylation / transcription regulator complex / DNA replication / chromosome, telomeric region / endosome / chromatin remodeling / cell division / protein domain specific binding / protein phosphorylation / DNA repair / protein serine kinase activity / centrosome / protein serine/threonine kinase activity / DNA-templated transcription / positive regulation of cell population proliferation / positive regulation of DNA-templated transcription / magnesium ion binding / negative regulation of transcription by RNA polymerase II / signal transduction / nucleoplasm / ATP binding / nucleus / cytosol / cytoplasm
Similarity search - Function
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, ATP binding site / Protein kinases ATP-binding region signature. ...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, 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-HDY / Cyclin-dependent kinase 2
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.91 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
Remark 700 SHEET THE SHEET STRUCTURE OF THIS MOLECULE IS BIFURCATED. IN ORDER TO REPRESENT THIS FEATURE IN ... SHEET THE SHEET STRUCTURE OF THIS MOLECULE IS BIFURCATED. IN ORDER TO REPRESENT THIS FEATURE IN THE SHEET RECORDS BELOW, TWO SHEETS ARE DEFINED.

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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)34,4642
Polymers34,0461
Non-polymers4181
Water2,216123
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
Unit cell
Length a, b, c (Å)53.529, 72.239, 72.137
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: 34045.531 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-HDY / 1-(DIMETHYLAMINO)-3-(4-{{4-(2-METHYLIMIDAZO[1,2-A]PYRIDIN-3-YL)PYRIMIDIN-2-YL]AMINO}PHENOXY)PROPAN-2-OL


Mass: 418.492 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H26N6O2
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 123 / Source method: isolated from a natural source / Formula: H2O
Compound detailsFUNCTION: PROBABLY INVOLVED IN THE CONTROL OF THE CELL CYCLE. INTERACTS WITH CYCLINS A, D, OR E. ...FUNCTION: PROBABLY INVOLVED IN THE CONTROL OF THE CELL CYCLE. INTERACTS WITH CYCLINS A, D, OR E. ACTIVITY OF CDK2 IS MAXIMAL DURING S PHASE AND G2.

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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: 0.875
DetectorType: MARRESEARCH / Detector: IMAGE PLATE / Date: Jul 15, 1998
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.875 Å / Relative weight: 1
ReflectionResolution: 1.91→43.03 Å / Num. obs: 20394 / % possible obs: 84.8 % / Redundancy: 2.2 % / Rmerge(I) obs: 0.066 / Net I/σ(I): 21.7
Reflection shellResolution: 1.9→2.01 Å / Redundancy: 2 % / Rmerge(I) obs: 0.137 / Mean I/σ(I) obs: 10.3 / % possible all: 73.3
Reflection
*PLUS
Highest resolution: 1.91 Å / Num. measured all: 95201 / Rmerge(I) obs: 0.052

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Processing

Software
NameClassification
REFMACrefinement
MOSFLMdata reduction
SCALAdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.91→43.03 Å / SU B: 3.881 / SU ML: 0.114 / Cross valid method: THROUGHOUT / ESU R: 0.223 / ESU R Free: 0.18 / Details: TLS REFINEMENT CARRIED OUT
RfactorNum. reflection% reflectionSelection details
Rfree0.241 979 5.1 %RANDOM
Rwork0.204 ---
obs0.205 18120 87.38 %-
Displacement parametersBiso mean: 16.54 Å2
Baniso -1Baniso -2Baniso -3
1-0.83 Å20 Å20 Å2
2---0.23 Å20 Å2
3----0.6 Å2
Refinement stepCycle: LAST / Resolution: 1.91→43.03 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2285 0 31 123 2439
Refinement
*PLUS
% reflection Rfree: 5 % / Rfactor Rfree: 0.237 / Rfactor Rwork: 0.197
Solvent computation
*PLUS
Displacement parameters
*PLUS

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