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- PDB-6oqi: CDK2 in complex with Cpd14 (5-fluoro-4-(4-methyl-5,6,7,8-tetrahyd... -

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Basic information

Entry
Database: PDB / ID: 6oqi
TitleCDK2 in complex with Cpd14 (5-fluoro-4-(4-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-3-yl)-N-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)pyrimidin-2-amine)
ComponentsCyclin-dependent kinase 2
KeywordsTRANSFERASE/TRANSFERASE inhibitor / kinase / TRANSFERASE / TRANSFERASE-TRANSFERASE inhibitor complex
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 / 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 / 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 / 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 / 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-N14 / Cyclin-dependent kinase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2 Å
AuthorsMurray, J.M.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2019
Title: Design of a brain-penetrant CDK4/6 inhibitor for glioblastoma.
Authors: Bronner, S.M. / Merrick, K.A. / Murray, J. / Salphati, L. / Moffat, J.G. / Pang, J. / Sneeringer, C.J. / Dompe, N. / Cyr, P. / Purkey, H. / Boenig, G.L. / Li, J. / Kolesnikov, A. / Larouche- ...Authors: Bronner, S.M. / Merrick, K.A. / Murray, J. / Salphati, L. / Moffat, J.G. / Pang, J. / Sneeringer, C.J. / Dompe, N. / Cyr, P. / Purkey, H. / Boenig, G.L. / Li, J. / Kolesnikov, A. / Larouche-Gauthier, R. / Lai, K.W. / Shen, X. / Aubert-Nicol, S. / Chen, Y.C. / Cheong, J. / Crawford, J.J. / Hafner, M. / Haghshenas, P. / Jakalian, A. / Leclerc, J.P. / Lim, N.K. / O'Brien, T. / Plise, E.G. / Shalan, H. / Sturino, C. / Wai, J. / Xiao, Y. / Yin, J. / Zhao, L. / Gould, S. / Olivero, A. / Heffron, T.P.
History
DepositionApr 26, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 29, 2020Provider: repository / Type: Initial release
Revision 1.1Aug 11, 2021Group: Database references / Category: citation / citation_author / database_2
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _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 / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.2Oct 11, 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

Downloads & links

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Assembly

Deposited unit
A: Cyclin-dependent kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,5602
Polymers34,1241
Non-polymers4371
Water1,856103
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)53.460, 72.090, 71.600
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: Trichoplusia ni (cabbage looper) / References: UniProt: P24941, cyclin-dependent kinase
#2: Chemical ChemComp-N14 / 5-fluoro-N-[5-(4-methylpiperazin-1-yl)pyridin-2-yl]-4-[(4S)-4-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-3-yl]pyrimidin-2-amine


Mass: 436.528 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H29FN8 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 103 / 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: 2.03 Å3/Da / Density % sol: 39.45 %
Crystal growTemperature: 292 K / Method: evaporation / pH: 7.5
Details: 10-12% PEG 4K, 50 mM Hepes pH7.5, 50 mM Ammonia Acetate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 0.999 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Feb 28, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.999 Å / Relative weight: 1
ReflectionResolution: 1.858→42.941 Å / Num. obs: 23997 / % possible obs: 100 % / Redundancy: 12.7 % / Biso Wilson estimate: 35.72 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.12 / Rpim(I) all: 0.035 / Rrim(I) all: 0.125 / Net I/σ(I): 13.4 / Num. measured all: 305459
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
1.858-1.86512.74.24530482400.351.2334.4240.799.2
8.603-42.94110.90.03132172960.9990.0090.03244.199.7

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
XDSdata reduction
Aimlessdata scaling
PHASERphasing
PHENIX1.13_2998refinement
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1AQA

1aqa


Resolution: 2→42.941 Å / SU ML: 0.31 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 28.06
RfactorNum. reflection% reflection
Rfree0.2411 1007 5.22 %
Rwork0.1975 --
obs0.1998 19290 99.98 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 177.65 Å2 / Biso mean: 53.7083 Å2 / Biso min: 19.29 Å2
Refinement stepCycle: final / Resolution: 2→42.941 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2339 0 32 103 2474
Biso mean--44.4 48.54 -
Num. residues----290
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 7 / % reflection obs: 100 %

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all
2-2.10550.36431340.332925622696
2.1055-2.23740.32331570.26525692726
2.2374-2.41010.26261420.234425672709
2.4101-2.65260.28731430.213225722715
2.6526-3.03640.26851560.220925892745
3.0364-3.82520.22291330.187826602793
3.8252-42.95090.20261420.160627642906
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.0307-0.2743-0.18481.52040.83520.4696-0.24930.5415-0.0427-0.87950.1132-1.0051-0.0777-0.12990.06070.44260.1670.08030.553-0.10570.613720.1032-16.03478.6804
21.2605-0.3556-0.29870.38810.0050.72680.1075-0.6256-0.15750.1436-0.0877-0.2875-0.19930.3573-0.00010.3691-0.0594-0.04230.52990.0250.536522.8335-12.651816.4443
31.7079-0.6266-0.68963.7570.40391.238-0.0896-0.1686-0.30110.15720.087-0.01320.04320.108400.2681-0.0212-0.02750.25820.05150.243710.4065-3.485516.4095
41.31881.05570.29962.3196-1.08081.67990.0230.0379-0.2903-0.28860.0209-0.43060.17470.29920.02160.36040.02660.0380.3455-0.01240.28415.39326.31738.9139
51.98180.7224-0.56432.2934-0.65241.02150.12350.16730.2121-0.1165-0.00680.1763-0.1395-0.04470.00020.25510.01370.01530.24880.0050.25255.503215.96489.7983
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 0 through 18 )A0 - 18
2X-RAY DIFFRACTION2chain 'A' and (resid 19 through 57 )A19 - 57
3X-RAY DIFFRACTION3chain 'A' and (resid 58 through 140 )A58 - 140
4X-RAY DIFFRACTION4chain 'A' and (resid 141 through 198 )A141 - 198
5X-RAY DIFFRACTION5chain 'A' and (resid 199 through 298 )A199 - 298

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