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- PDB-7rwf: Crystal structure of CDK2 in complex with TW8672 -

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Basic information

Entry
Database: PDB / ID: 7rwf
TitleCrystal structure of CDK2 in complex with TW8672
ComponentsCyclin-dependent kinase 2
KeywordsCELL CYCLE / Serine/threonine-protein kinase DNA repair Meiosis allosteric inhibitor drug development
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-7TW / Cyclin-dependent kinase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.5 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
DepositionAug 19, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 24, 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)34,5113
Polymers34,1241
Non-polymers3872
Water2,972165
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)50.798, 72.237, 71.436
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: 34123.660 Da / Num. of mol.: 1 / Fragment: kinase domain
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-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#3: Chemical ChemComp-7TW / 2-{[2-(1H-indol-3-yl)ethyl]amino}-5-nitrobenzoic acid


Mass: 325.319 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H15N3O4 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 165 / 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: 1.92 Å3/Da / Density % sol: 35.95 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 4.5mg/mL, 15% Jeffamine ED-2001, 0.1M HEPES pH7.5, VAPOR DIFFUSION, HANGING DROP, temperature 291K

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Data collection

DiffractionMean temperature: 173 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.54178 Å
DetectorType: RIGAKU SATURN 944+ / Detector: CCD / Date: Oct 2, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54178 Å / Relative weight: 1
ReflectionResolution: 1.5→50 Å / Num. obs: 42853 / % possible obs: 99.9 % / Redundancy: 4.1 % / Rmerge(I) obs: 0.1 / Rpim(I) all: 0.045 / Rrim(I) all: 0.11 / Χ2: 7.075 / Net I/σ(I): 19.4 / Num. measured all: 174799
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
1.5-1.532.40.36120750.7870.2880.4640.45898.9
1.53-1.552.50.31221030.8390.2420.3970.49899.7
1.55-1.582.60.28721130.8710.2170.3620.506100
1.58-1.622.70.25921080.8990.1930.3240.536100
1.62-1.652.80.22821290.910.1650.2820.601100
1.65-1.692.90.19621160.9350.140.2420.633100
1.69-1.7330.1821010.9580.1260.2210.71100
1.73-1.783.10.15721290.960.1070.1910.837100
1.78-1.833.20.13821260.9710.0910.1660.997100
1.83-1.893.30.12121250.9770.0780.1441.161100
1.89-1.963.40.10821380.9780.0680.1281.59100
1.96-2.043.70.1521360.9580.0850.1737.359100
2.04-2.134.30.221130.9330.1060.22713.732100
2.13-2.244.50.18521390.9520.0960.20914.564100
2.24-2.384.70.17421520.9580.0880.19514.24100
2.38-2.565.10.16721540.960.0820.18613.601100
2.56-2.825.70.15121760.9730.0690.16712.187100
2.82-3.237.10.13221670.9870.0540.14310.851100
3.23-4.077.10.08522110.9940.0340.0927.313100
4.07-506.70.05223420.9970.0220.0573.859100

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Processing

Software
NameVersionClassification
PHENIX1.18.2_3874refinement
HKL-2000data scaling
PDB_EXTRACT3.27data extraction
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4kd1

4kd1


Resolution: 1.5→41.55 Å / SU ML: 0.14 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 19.04 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2093 1995 4.66 %
Rwork0.1917 40796 -
obs0.1925 42791 99.83 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 55.4 Å2 / Biso mean: 21.0979 Å2 / Biso min: 9.73 Å2
Refinement stepCycle: final / Resolution: 1.5→41.55 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2409 0 28 165 2602
Biso mean--19.32 26.09 -
Num. residues----299
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 14

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.5-1.540.22291390.22322817295698
1.54-1.580.20681410.204328693010100
1.58-1.620.2711380.199228703008100
1.62-1.680.23721400.188628623002100
1.68-1.740.18561430.190928943037100
1.74-1.810.2081470.197128973044100
1.81-1.890.22421380.193429023040100
1.89-1.990.21621400.195228863026100
1.99-2.110.25051470.197229163063100
2.11-2.280.20951420.191929003042100
2.28-2.510.21651410.194729293070100
2.51-2.870.21531400.208229543094100
2.87-3.610.20031460.196329843130100
3.61-41.550.18871530.17231163269100

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