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- PDB-6q4i: CDK2 in complex with FragLite35 -

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Basic information

Entry
Database: PDB / ID: 6q4i
TitleCDK2 in complex with FragLite35
ComponentsCyclin-dependent kinase 2
KeywordsCELL CYCLE / Fragment / FragLite / CDK2 / inhibitor
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
: / 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
Similarity search - Domain/homology
Chem-HGK / Cyclin-dependent kinase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.11 Å
AuthorsWood, D.J. / Martin, M.P. / Noble, M.E.M.
Funding support United Kingdom, 2items
OrganizationGrant numberCountry
Medical Research Council (United Kingdom)MR/N009738/1 United Kingdom
Cancer Research UKC2115/A21421 United Kingdom
CitationJournal: J.Med.Chem. / Year: 2019
Title: FragLites-Minimal, Halogenated Fragments Displaying Pharmacophore Doublets. An Efficient Approach to Druggability Assessment and Hit Generation.
Authors: Wood, D.J. / Lopez-Fernandez, J.D. / Knight, L.E. / Al-Khawaldeh, I. / Gai, C. / Lin, S. / Martin, M.P. / Miller, D.C. / Cano, C. / Endicott, J.A. / Hardcastle, I.R. / Noble, M.E.M. / Waring, M.J.
History
DepositionDec 5, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 20, 2019Provider: repository / Type: Initial release
Revision 1.1Apr 3, 2019Group: Data collection / Source and taxonomy / Category: entity_src_gen
Item: _entity_src_gen.pdbx_host_org_cell_line / _entity_src_gen.pdbx_host_org_ncbi_taxonomy_id / _entity_src_gen.pdbx_host_org_scientific_name
Revision 1.2Apr 24, 2019Group: Data collection / Database references
Category: citation / citation_author ...citation / citation_author / database_PDB_rev / database_PDB_rev_record / pdbx_database_proc
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.name
Revision 1.3Jan 24, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
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)35,1413
Polymers34,8171
Non-polymers3232
Water5,224290
1


  • Idetical with deposited unit
  • defined by software
  • Evidence: gel filtration, monomer
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area250 Å2
ΔGint3 kcal/mol
Surface area14400 Å2
MethodPISA
Unit cell
Length a, b, c (Å)53.314, 72.573, 72.038
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: 34817.457 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CDK2, CDKN2 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P24941, cyclin-dependent kinase
#2: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#3: Chemical ChemComp-HGK / 2-[4-[(2-oxidanylidene-3~{H}-pyridin-4-yl)oxy]phenyl]ethanoic acid


Mass: 245.231 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C13H11NO4 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 290 / 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 Å3/Da / Density % sol: 38.62 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.4
Details: 10MG/ML CDK2 10% V/V PEG3350, 50 MM HEPES/NAOH, 50 MM NA/K PHOSPHATE, PH 7.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I24 / Wavelength: 0.98 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 8, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 1.11→53.31 Å / Num. obs: 99386 / % possible obs: 89.8 % / Redundancy: 6.1 % / CC1/2: 0.99 / Rmerge(I) obs: 0.08 / Net I/σ(I): 11.4
Reflection shellResolution: 1.11→1.13 Å / Redundancy: 2.6 % / Rmerge(I) obs: 0.77 / Mean I/σ(I) obs: 1.4 / Num. unique obs: 4954 / CC1/2: 0.55 / % possible all: 44.3

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Processing

Software
NameVersionClassification
REFMAC5.8.0238refinement
xia2data reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1HCK

1hck


Resolution: 1.11→51.18 Å / Cor.coef. Fo:Fc: 0.969 / Cor.coef. Fo:Fc free: 0.962 / Cross valid method: THROUGHOUT / ESU R: 0.038 / ESU R Free: 0.038 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.19246 4954 5 %RANDOM
Rwork0.16487 ---
obs0.16624 94432 89.72 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 16.638 Å2
Baniso -1Baniso -2Baniso -3
1-0.86 Å20 Å20 Å2
2---0.37 Å20 Å2
3----0.49 Å2
Refinement stepCycle: 1 / Resolution: 1.11→51.18 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2330 0 22 290 2642
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.0132527
X-RAY DIFFRACTIONr_bond_other_d0.0340.0172438
X-RAY DIFFRACTIONr_angle_refined_deg1.8951.6443441
X-RAY DIFFRACTIONr_angle_other_deg2.3091.5745651
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.1115310
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.77921.22123
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.33315448
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.2911517
X-RAY DIFFRACTIONr_chiral_restr0.1140.2320
X-RAY DIFFRACTIONr_gen_planes_refined0.0120.022806
X-RAY DIFFRACTIONr_gen_planes_other0.0160.02549
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_it2.1061.4271213
X-RAY DIFFRACTIONr_mcbond_other2.0931.4271212
X-RAY DIFFRACTIONr_mcangle_it2.7592.1481532
X-RAY DIFFRACTIONr_mcangle_other2.7582.1481533
X-RAY DIFFRACTIONr_scbond_it2.7261.7941314
X-RAY DIFFRACTIONr_scbond_other2.7271.7941315
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other3.4562.5611910
X-RAY DIFFRACTIONr_long_range_B_refined3.86918.0922949
X-RAY DIFFRACTIONr_long_range_B_other3.86818.092950
X-RAY DIFFRACTIONr_rigid_bond_restr17.52534965
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.11→1.139 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.248 206 -
Rwork0.258 3487 -
obs--45.77 %

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