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- PDB-7s84: Crystal structure of CDK2 liganded with compound TW8972 -

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Basic information

Entry
Database: PDB / ID: 7s84
TitleCrystal structure of CDK2 liganded with compound TW8972
ComponentsCyclin-dependent kinase 2
KeywordsCELL CYCLE / allosteric inhibitor / drug development / 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 / 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 / Activation of ATR in response to replication stress / Regulation of MITF-M-dependent genes involved in cell cycle and proliferation / Cajal body / Cyclin E associated events during G1/S transition / Cyclin A:Cdk2-associated events at S phase entry / Cyclin A/B1/B2 associated events during G2/M transition / cyclin-dependent protein kinase holoenzyme complex / regulation of G2/M transition of mitotic cell cycle / condensed chromosome / mitotic G1 DNA damage checkpoint signaling / cellular response to nitric oxide / post-translational protein modification / regulation of mitotic cell cycle / cyclin binding / positive regulation of DNA replication / meiotic cell cycle / male germ cell nucleus / G1/S transition of mitotic cell cycle / peptidyl-serine phosphorylation / potassium ion transport / DNA Damage/Telomere Stress Induced Senescence / Meiotic recombination / CDK-mediated phosphorylation and removal of Cdc6 / G2/M transition of mitotic cell cycle / SCF(Skp2)-mediated degradation of p27/p21 / 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 / regulation of gene expression / Processing of DNA double-strand break ends / Senescence-Associated Secretory Phenotype (SASP) / transcription regulator complex / Regulation of TP53 Activity through Phosphorylation / Ras protein signal transduction / DNA replication / chromosome, telomeric region / 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-8IL / Cyclin-dependent kinase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsSun, L. / Schonbrunn, E.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health & Human Development (NIH/NICHD)1R61HD099743-01 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)P30CA076292 United States
CitationJournal: Nat Commun / Year: 2023
Title: Development of allosteric and selective CDK2 inhibitors for contraception with negative cooperativity to cyclin binding.
Authors: Faber, E.B. / Sun, L. / Tang, J. / Roberts, E. / Ganeshkumar, S. / Wang, N. / Rasmussen, D. / Majumdar, A. / Hirsch, L.E. / John, K. / Yang, A. / Khalid, H. / Hawkinson, J.E. / Levinson, N.M. ...Authors: Faber, E.B. / Sun, L. / Tang, J. / Roberts, E. / Ganeshkumar, S. / Wang, N. / Rasmussen, D. / Majumdar, A. / Hirsch, L.E. / John, K. / Yang, A. / Khalid, H. / Hawkinson, J.E. / Levinson, N.M. / Chennathukuzhi, V. / Harki, D.A. / Schonbrunn, E. / Georg, G.I.
History
DepositionSep 17, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 28, 2022Provider: repository / Type: Initial release
Revision 1.1Jun 14, 2023Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Oct 25, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)34,3252
Polymers33,9761
Non-polymers3481
Water2,450136
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)54.190, 71.550, 72.220
Angle α, β, γ (deg.)90.000, 90.000, 90.000
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: Escherichia coli (E. coli) / References: UniProt: P24941, cyclin-dependent kinase
#2: Chemical ChemComp-8IL / 2-{[2-(1H-indol-3-yl)ethyl]amino}-5-(trifluoromethyl)benzoic acid


Mass: 348.319 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H15F3N2O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 136 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.06 Å3/Da / Density % sol: 40.36 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop
Details: 4.5mg/mL CDK2 crystalized in 50mM Na/K phosphate, 50mM Hepes Na, pH7.5 5% v/v PEG3350, soaked for overnight in 5mM TW8972 in 0.1M HEPES Na pH7.5 10% v/v PEG3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 23-ID-B / Wavelength: 1.0332 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jul 13, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0332 Å / Relative weight: 1
ReflectionResolution: 2→100 Å / Num. obs: 19447 / % possible obs: 99.5 % / Redundancy: 6.2 % / Rrim(I) all: 0.119 / Net I/σ(I): 9.77
Reflection shell
Resolution (Å)Mean I/σ(I) obsNum. unique obsCC1/2Rrim(I) allDiffraction-ID% possible all
2-2.052.0713900.8850.751199.2
2.05-2.112.3813800.8960.751199.3
2.11-2.173.0413440.9190.535199
2.17-2.243.6312900.9460.447199.2
2.24-2.314.1112790.9510.396199.3
2.31-2.394.8612090.9610.337199.3
2.39-2.485.2411980.9590.311199.3
2.48-2.586.1511350.970.259199
2.58-2.77.2810930.9810.222199.6
2.7-2.837.2810550.9810.222199.6
2.83-2.9810.5510100.990.162199.8
2.98-3.1612.669480.9920.134199.7
3.16-3.3815.649110.9950.107199.7
3.38-3.6519.298360.9960.086199.9
3.65-47820.9970.0731100
4-4.477260.9970.066199.9
4.47-5.166250.9970.063199.4
5.16-6.325380.9960.068199.1
6.32-8.944450.9980.053199.8
8.94-1002530.9990.043198.1

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Processing

Software
NameVersionClassification
PHENIX1.18.2-3874_3874refinement
HKL-2000data scaling
PDB_EXTRACT3.27data extraction
HKL-2000data reduction
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4dk1

4dk1


Resolution: 2→43.2 Å / SU ML: 0.25 / Cross valid method: THROUGHOUT / σ(F): 1.37 / Phase error: 26.06 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2441 1458 7.5 %
Rwork0.1968 17981 -
obs0.2003 19439 99.35 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 86.75 Å2 / Biso mean: 35.3359 Å2 / Biso min: 16.85 Å2
Refinement stepCycle: final / Resolution: 2→43.2 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2217 0 25 136 2378
Biso mean--33.96 38.81 -
Num. residues----282
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 10

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2-2.070.30921410.22481735187698
2.07-2.150.29931440.22041773191799
2.15-2.250.29961440.21741774191899
2.25-2.370.29011430.21121766190999
2.37-2.520.29711430.21531768191199
2.52-2.710.27411440.21031777192199
2.71-2.990.26541470.211418131960100
2.99-3.420.24321460.205718131959100
3.42-4.310.20991490.1718341983100
4.31-43.20.20931570.18641928208599

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