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- PDB-9gla: Crystal structure of a CDK2-based CDK7 mimic with inhibitor SY5609 -

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Basic information

Entry
Database: PDB / ID: 9gla
TitleCrystal structure of a CDK2-based CDK7 mimic with inhibitor SY5609
Components
  • Cyclin-A2
  • Cyclin-dependent kinase 2
KeywordsCELL CYCLE / cyclin-dependent kinase / inhibitor / SY5609 / selectivity / structure-assisted inhibitor design
Function / homology
Function and homology information


: / cyclin A2-CDK1 complex / cellular response to luteinizing hormone stimulus / cell cycle G1/S phase transition / Transcription of E2F targets under negative control by p107 (RBL1) and p130 (RBL2) in complex with HDAC1 / cellular response to leptin stimulus / male pronucleus / female pronucleus / response to glucagon / cellular response to cocaine ...: / cyclin A2-CDK1 complex / cellular response to luteinizing hormone stimulus / cell cycle G1/S phase transition / Transcription of E2F targets under negative control by p107 (RBL1) and p130 (RBL2) in complex with HDAC1 / cellular response to leptin stimulus / male pronucleus / female pronucleus / response to glucagon / cellular response to cocaine / cyclin-dependent protein serine/threonine kinase regulator activity / positive regulation of DNA biosynthetic process / cellular response to insulin-like growth factor stimulus / cyclin A1-CDK2 complex / cyclin E2-CDK2 complex / cyclin E1-CDK2 complex / cochlea development / cyclin A2-CDK2 complex / positive regulation of DNA-templated DNA replication initiation / cyclin-dependent protein kinase activity / G2 Phase / 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) / microtubule organizing center / centriole replication / Regulation of APC/C activators between G1/S and early anaphase / telomere maintenance in response to DNA damage / regulation of DNA replication / centrosome duplication / Telomere Extension By Telomerase / G0 and Early G1 / Activation of the pre-replicative complex / cyclin-dependent kinase / animal organ regeneration / 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 / cellular response to platelet-derived growth factor stimulus / mitotic G1 DNA damage checkpoint signaling / cellular response to nitric oxide / post-translational protein modification / cyclin binding / regulation of mitotic cell cycle / male germ cell nucleus / positive regulation of DNA replication / meiotic cell cycle / Cdc20:Phospho-APC/C mediated degradation of Cyclin A / cellular response to estradiol stimulus / potassium ion transport / DNA Damage/Telomere Stress Induced Senescence / Meiotic recombination / CDK-mediated phosphorylation and removal of Cdc6 / SCF(Skp2)-mediated degradation of p27/p21 / G1/S transition of mitotic cell cycle / Transcriptional regulation of granulopoiesis / Orc1 removal from chromatin / positive regulation of fibroblast proliferation / G2/M transition of mitotic cell cycle / Cyclin D associated events in G1 / cellular senescence / Regulation of TP53 Degradation / nuclear envelope / peptidyl-serine phosphorylation / Factors involved in megakaryocyte development and platelet production / Processing of DNA double-strand break ends / regulation of gene expression / Senescence-Associated Secretory Phenotype (SASP) / cellular response to hypoxia / Regulation of TP53 Activity through Phosphorylation / transcription regulator complex / Ras protein signal transduction / chromosome, telomeric region / DNA replication / endosome / Ub-specific processing proteases / protein phosphorylation / chromatin remodeling / protein domain specific binding / cell division / protein serine kinase activity / DNA repair / protein serine/threonine kinase activity / DNA-templated transcription / positive regulation of cell population proliferation / centrosome / protein kinase binding
Similarity search - Function
Cyclin-A, N-terminal APC/C binding region / Cyclin-A N-terminal APC/C binding region / : / Cyclin, C-terminal domain / : / Cyclins signature. / Cyclin / Cyclin, C-terminal domain / Cyclin_C / Cyclin, N-terminal ...Cyclin-A, N-terminal APC/C binding region / Cyclin-A N-terminal APC/C binding region / : / Cyclin, C-terminal domain / : / Cyclins signature. / Cyclin / Cyclin, C-terminal domain / Cyclin_C / Cyclin, N-terminal / Cyclin, N-terminal domain / Cyclin-like / domain present in cyclins, TFIIB and Retinoblastoma / Cyclin-like superfamily / : / 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
MONOTHIOGLYCEROL / : / Cyclin-A2 / Cyclin-dependent kinase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.18 Å
AuthorsSkerlova, J. / Krejcirikova, V. / Rezacova, P.
Funding supportEuropean Union, 1items
OrganizationGrant numberCountry
European Union (EU)Programme EXCELES, ID Project No. LX22NPO5102European Union
CitationJournal: Int.J.Biol.Macromol. / Year: 2025
Title: CDK2-based CDK7 mimic as a tool for structural analysis: Biochemical validation and crystal structure with SY5609.
Authors: Skerlova, J. / Krejcirikova, V. / Perina, M. / Vojackova, V. / Fabry, M. / Krystof, V. / Jorda, R. / Rezacova, P.
History
DepositionAug 27, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 2, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Cyclin-dependent kinase 2
B: Cyclin-A2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,2926
Polymers63,6482
Non-polymers6454
Water1,892105
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3670 Å2
ΔGint-38 kcal/mol
Surface area23580 Å2
Unit cell
Length a, b, c (Å)71.937, 109.786, 163.554
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221

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Components

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Protein , 2 types, 2 molecules AB

#1: Protein Cyclin-dependent kinase 2 / Cell division protein kinase 2 / p33 protein kinase


Mass: 34023.328 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: CDK2 containing 12 active-site mutations mimicking CDK7: E8D, K9F, I10L, T14Q, Y15F, V64I, L83M, H84E, Q85T, K88E, K89V, Q131N
Source: (gene. exp.) Homo sapiens (human) / Gene: CDK2, CDKN2 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P24941, cyclin-dependent kinase
#2: Protein Cyclin-A2 / Cyclin-A / Cyclin A


Mass: 29624.297 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CCNA2, CCN1, CCNA / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P20248

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Non-polymers , 4 types, 109 molecules

#3: Chemical ChemComp-YNK / 7-dimethylphosphoryl-3-[2-[[(3~{S})-6,6-dimethylpiperidin-3-yl]amino]-5-(trifluoromethyl)pyrimidin-4-yl]-1~{H}-indole-6-carbonitrile


Mass: 490.461 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H26F3N6OP / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-SGM / MONOTHIOGLYCEROL


Mass: 108.159 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O2S
#5: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Na
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 105 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationY

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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: 2.54 Å3/Da / Density % sol: 51.51 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 7 / Details: 0.8 M succinic acid pH 7.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SOLEIL / Beamline: PROXIMA 2 / Wavelength: 0.98011 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Jul 8, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98011 Å / Relative weight: 1
ReflectionResolution: 2.18→48.47 Å / Num. obs: 33815 / % possible obs: 99.3 % / Redundancy: 13.3 % / CC1/2: 0.996 / Rmerge(I) obs: 0.322 / Rrim(I) all: 0.335 / Net I/σ(I): 9.47
Reflection shell
Resolution (Å)Num. unique obsCC1/2Diffraction-ID% possible all
2.18-2.3152450.358197.1
2.31-2.4750870.6241
2.47-2.6745730.8011
2.67-2.9343830.9091
2.93-3.2740180.9741
3.27-3.7735250.9921
3.77-4.6130220.9961
4.61-6.523840.9971
6.5-48.4713980.9981

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Processing

Software
NameVersionClassification
REFMAC5.8.0405refinement
XDSdata scaling
MOLREPphasing
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.18→48.46 Å / Cor.coef. Fo:Fc: 0.965 / Cor.coef. Fo:Fc free: 0.947 / Cross valid method: THROUGHOUT / ESU R: 0.265 / ESU R Free: 0.212 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.24906 1685 5 %RANDOM
Rwork0.20109 ---
obs0.20348 32030 99.05 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 53.112 Å2
Baniso -1Baniso -2Baniso -3
1--3.4 Å20 Å2-0 Å2
2--5.49 Å20 Å2
3----2.09 Å2
Refinement stepCycle: 1 / Resolution: 2.18→48.46 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4430 0 42 105 4577
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0124687
X-RAY DIFFRACTIONr_bond_other_d0.0010.0164486
X-RAY DIFFRACTIONr_angle_refined_deg1.3491.6646388
X-RAY DIFFRACTIONr_angle_other_deg0.8221.57810363
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.355571
X-RAY DIFFRACTIONr_dihedral_angle_2_deg3.034523
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.14310814
X-RAY DIFFRACTIONr_dihedral_angle_4_deg
X-RAY DIFFRACTIONr_chiral_restr0.0610.2714
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.025351
X-RAY DIFFRACTIONr_gen_planes_other0.0060.021040
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_it3.7475.1122254
X-RAY DIFFRACTIONr_mcbond_other3.7445.1122254
X-RAY DIFFRACTIONr_mcangle_it5.7269.2132832
X-RAY DIFFRACTIONr_mcangle_other5.7269.2152833
X-RAY DIFFRACTIONr_scbond_it4.5765.6912433
X-RAY DIFFRACTIONr_scbond_other4.5755.6942434
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other7.38510.2263556
X-RAY DIFFRACTIONr_long_range_B_refined9.61848.345251
X-RAY DIFFRACTIONr_long_range_B_other9.62348.355243
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.183→2.239 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.572 110 -
Rwork0.579 2112 -
obs--90.07 %

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