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- PDB-5iey: Crystal structure of a CDK inhibitor bound to CDK2 -

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Basic information

Entry
Database: PDB / ID: 5iey
TitleCrystal structure of a CDK inhibitor bound to CDK2
ComponentsCyclin-dependent kinase 2
KeywordsTRANSFERASE / Antineoplastic Agents / Cyclin-Dependent Kinases / Dose-Response Relationship / Drug / Drug Discovery / HeLa Cells / Molecular Structure / Neoplasms / Protein Kinase Inhibitors / Pyrimidines / Structure-Activity Relationship / Structure-Kinetics Relationship / Sulfoxides / Biophysical Assays / Tumor / Humans
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 / telomere maintenance in response to DNA damage / centrosome duplication / G0 and Early G1 / Telomere Extension By Telomerase / cellular response to nitric oxide / 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 / Cyclin E associated events during G1/S transition / Cajal body / Cyclin A/B1/B2 associated events during G2/M transition / cyclin-dependent protein kinase holoenzyme complex / mitotic G1 DNA damage checkpoint signaling / Cyclin A:Cdk2-associated events at S phase entry / condensed chromosome / regulation of G2/M transition of mitotic cell cycle / regulation of mitotic cell cycle / 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 / Orc1 removal from chromatin / Transcriptional regulation of granulopoiesis / G1/S transition of mitotic cell cycle / 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) / peptidyl-serine phosphorylation / regulation of gene expression / Regulation of TP53 Activity through Phosphorylation / transcription regulator complex / Ras protein signal transduction / DNA replication / chromosome, telomeric region / endosome / chromatin remodeling / protein phosphorylation / protein domain specific binding / cell division / protein serine kinase activity / DNA repair / protein serine/threonine kinase activity / centrosome / DNA-templated transcription / 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
: / 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 ...: / 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-6AE / Cyclin-dependent kinase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.66 Å
AuthorsAyaz, P. / Andres, D. / Kwiatkowski, D.A. / Kolbe, C. / Lienau, P. / Siemeister, G. / Luecking, U. / Stegmann, C.M.
CitationJournal: Acs Chem.Biol. / Year: 2016
Title: Conformational Adaption May Explain the Slow Dissociation Kinetics of Roniciclib (BAY 1000394), a Type I CDK Inhibitor with Kinetic Selectivity for CDK2 and CDK9.
Authors: Ayaz, P. / Andres, D. / Kwiatkowski, D.A. / Kolbe, C.C. / Lienau, P. / Siemeister, G. / Lucking, U. / Stegmann, C.M.
History
DepositionFeb 25, 2016Deposition site: RCSB / Processing site: PDBE
Revision 1.0Apr 27, 2016Provider: repository / Type: Initial release
Revision 1.1May 4, 2016Group: Database references
Revision 1.2Jun 29, 2016Group: Database references
Revision 1.3Oct 16, 2019Group: Data collection / Category: reflns_shell
Revision 1.4May 8, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Cyclin-dependent kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,3142
Polymers33,9761
Non-polymers3371
Water3,459192
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area14140 Å2
MethodPISA
Unit cell
Length a, b, c (Å)53.337, 71.983, 72.037
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 Cyclin-dependent kinase 2 / Cell division protein kinase 2 / p33 protein kinase


Mass: 33976.488 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CDK2, CDKN2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P24941, cyclin-dependent kinase
#2: Chemical ChemComp-6AE / 4-[(4-{[(2R,3R)-3-hydroxybutan-2-yl]amino}pyrimidin-2-yl)amino]benzene-1-sulfonamide


Mass: 337.397 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H19N5O3S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 192 / 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: 2.02 Å3/Da / Density % sol: 39.18 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, hanging drop / pH: 7.8
Details: 7.25% PEG 4000, 0.2 M ammonium acetate, 0.2 M HEPES pH 7.8

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.1 / Wavelength: 0.918 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.918 Å / Relative weight: 1
ReflectionResolution: 1.66→42.87 Å / Num. obs: 30887 / % possible obs: 97.8 % / Redundancy: 4.25 % / Net I/σ(I): 10.69

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Processing

Software
NameVersionClassification
REFMAC5.8.0049refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.66→42.87 Å / Cor.coef. Fo:Fc: 0.962 / Cor.coef. Fo:Fc free: 0.948 / SU B: 5.564 / SU ML: 0.094 / Cross valid method: THROUGHOUT / ESU R: 0.108 / ESU R Free: 0.11 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.22502 1626 5 %RANDOM
Rwork0.17963 ---
obs0.18192 30887 97.8 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 39.682 Å2
Baniso -1Baniso -2Baniso -3
1--0.86 Å20 Å2-0 Å2
2--2.08 Å2-0 Å2
3----1.22 Å2
Refinement stepCycle: 1 / Resolution: 1.66→42.87 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2296 0 23 192 2511
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0180.0192430
X-RAY DIFFRACTIONr_bond_other_d0.0020.022398
X-RAY DIFFRACTIONr_angle_refined_deg1.9491.9843303
X-RAY DIFFRACTIONr_angle_other_deg0.9773.0015506
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.0835297
X-RAY DIFFRACTIONr_dihedral_angle_2_deg41.78523.039102
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.89915427
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.1961516
X-RAY DIFFRACTIONr_chiral_restr0.1290.2370
X-RAY DIFFRACTIONr_gen_planes_refined0.0110.0212683
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02557
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_it2.2982.6211164
X-RAY DIFFRACTIONr_mcbond_other2.2982.6211163
X-RAY DIFFRACTIONr_mcangle_it3.153.9121457
X-RAY DIFFRACTIONr_mcangle_other3.1493.9121458
X-RAY DIFFRACTIONr_scbond_it3.1542.9751266
X-RAY DIFFRACTIONr_scbond_other3.1532.9751267
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other4.6214.331843
X-RAY DIFFRACTIONr_long_range_B_refined7.66522.6512915
X-RAY DIFFRACTIONr_long_range_B_other7.65422.1632839
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.664→1.707 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.378 103 -
Rwork0.27 1950 -
obs--85.4 %
Refinement TLS params.Method: refined / Origin x: 1.6875 Å / Origin y: -5.2118 Å / Origin z: -14.5553 Å
111213212223313233
T0.0925 Å20.0139 Å2-0.0019 Å2-0.0452 Å20.0067 Å2--0.027 Å2
L1.1027 °20.3327 °2-0.1433 °2-0.4578 °20.1147 °2--1.8633 °2
S0.0439 Å °0.0461 Å °0.0174 Å °-0.0181 Å °-0.0352 Å °0.0857 Å °0.0262 Å °-0.0388 Å °-0.0087 Å °

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