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- PDB-6q4k: CDK2 in complex with FragLite38 -

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Basic information

Entry
Database: PDB / ID: 6q4k
TitleCDK2 in complex with FragLite38
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 / Y chromosome / cyclin-dependent protein kinase activity / 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 / Y chromosome / cyclin-dependent protein kinase activity / 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 / 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 / Cajal body / Activation of ATR in response to replication stress / 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 / cyclin-dependent protein kinase holoenzyme complex / condensed chromosome / regulation of G2/M transition of mitotic cell cycle / mitotic G1 DNA damage checkpoint signaling / cellular response to nitric oxide / post-translational protein modification / cyclin binding / regulation of mitotic cell cycle / positive regulation of DNA replication / meiotic cell cycle / male germ cell nucleus / G1/S transition of mitotic cell cycle / peptidyl-serine phosphorylation / DNA Damage/Telomere Stress Induced Senescence / potassium ion transport / CDK-mediated phosphorylation and removal of Cdc6 / Meiotic recombination / SCF(Skp2)-mediated degradation of p27/p21 / G2/M transition of mitotic cell cycle / Transcriptional regulation of granulopoiesis / Orc1 removal from chromatin / 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 / regulation of gene expression / Senescence-Associated Secretory Phenotype (SASP) / transcription regulator complex / Regulation of TP53 Activity through Phosphorylation / Ras protein signal transduction / chromosome, telomeric region / DNA replication / protein phosphorylation / endosome / chromatin remodeling / protein domain specific binding / cell division / protein serine kinase activity / DNA repair / protein serine/threonine kinase activity / positive regulation of cell population proliferation / DNA-templated transcription / centrosome / 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
: / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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 ...: / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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-HHW / Cyclin-dependent kinase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.06 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 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 1.2Jan 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)35,4274
Polymers34,7611
Non-polymers6663
Water5,711317
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration, monomer
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area230 Å2
ΔGint3 kcal/mol
Surface area14770 Å2
MethodPISA
Unit cell
Length a, b, c (Å)52.897, 71.265, 72.062
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: 34761.348 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-HHW / (~{E})-3-[3-[(4-chlorophenyl)carbamoyl]phenyl]prop-2-enoic acid


Mass: 301.724 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C16H12ClNO3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 317 / 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: 1.95 Å3/Da / Density % sol: 37.04 %
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: I04 / Wavelength: 0.98 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 5, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 1.06→72.07 Å / Num. obs: 105138 / % possible obs: 84.3 % / Redundancy: 5.7 % / CC1/2: 0.99 / Rmerge(I) obs: 0.026 / Net I/σ(I): 24.7
Reflection shellResolution: 1.06→1.08 Å / Redundancy: 1.1 % / Rmerge(I) obs: 0.56 / Mean I/σ(I) obs: 0.8 / Num. unique obs: 5230 / CC1/2: 0.61 / % possible all: 5.5

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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: 1.06→50.72 Å / Cor.coef. Fo:Fc: 0.975 / Cor.coef. Fo:Fc free: 0.974 / Cross valid method: THROUGHOUT / ESU R: 0.032 / ESU R Free: 0.031 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.16216 5230 5 %RANDOM
Rwork0.14312 ---
obs0.14407 99908 84.27 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 19.66 Å2
Baniso -1Baniso -2Baniso -3
1--0.56 Å2-0 Å20 Å2
2--0.59 Å2-0 Å2
3----0.03 Å2
Refinement stepCycle: 1 / Resolution: 1.06→50.72 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2358 0 46 317 2721
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0132570
X-RAY DIFFRACTIONr_bond_other_d0.0330.0172483
X-RAY DIFFRACTIONr_angle_refined_deg1.8811.6463496
X-RAY DIFFRACTIONr_angle_other_deg2.3211.5745754
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.1855316
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.59120.787127
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.28215455
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.8131518
X-RAY DIFFRACTIONr_chiral_restr0.1090.2321
X-RAY DIFFRACTIONr_gen_planes_refined0.0120.022854
X-RAY DIFFRACTIONr_gen_planes_other0.0160.02572
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_it2.3171.6911210
X-RAY DIFFRACTIONr_mcbond_other2.3121.691209
X-RAY DIFFRACTIONr_mcangle_it2.992.5371523
X-RAY DIFFRACTIONr_mcangle_other2.9892.5391524
X-RAY DIFFRACTIONr_scbond_it3.3432.1541360
X-RAY DIFFRACTIONr_scbond_other3.3422.1551361
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other4.0413.0741967
X-RAY DIFFRACTIONr_long_range_B_refined4.67322.1083081
X-RAY DIFFRACTIONr_long_range_B_other4.67322.1083082
X-RAY DIFFRACTIONr_rigid_bond_restr11.88235053
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.057→1.085 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.224 46 -
Rwork0.298 794 -
obs--9.24 %

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