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- PDB-6gue: CDK2/CyclinA in complex with AZD5438 -

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Basic information

Entry
Database: PDB / ID: 6gue
TitleCDK2/CyclinA in complex with AZD5438
Components
  • (Cyclin-dependent kinase 2) x 2
  • Cyclin-A2
KeywordsCELL CYCLE / CDK2 / CYCLINA / INHIBITOR
Function / homology
Function and homology information


cell cycle G1/S phase transition / cyclin-dependent protein serine/threonine kinase regulator activity / 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 ...cell cycle G1/S phase transition / cyclin-dependent protein serine/threonine kinase regulator activity / 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 / microtubule organizing center / regulation of DNA replication / 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 / Cajal body / Regulation of MITF-M-dependent genes involved in cell cycle and proliferation / 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 / Orc1 removal from chromatin / Transcriptional regulation of granulopoiesis / 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 / cytoplasm / cytosol
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-like / Cyclin, C-terminal domain / Cyclin_C ...Cyclin-A, N-terminal APC/C binding region / Cyclin-A N-terminal APC/C binding region / : / Cyclin, C-terminal domain / : / Cyclins signature. / Cyclin / Cyclin-like / Cyclin, C-terminal domain / Cyclin_C / Cyclin A; domain 1 / Cyclin, N-terminal / Cyclin, N-terminal domain / Cyclin-like / domain present in cyclins, TFIIB and Retinoblastoma / Cyclin-like superfamily / : / 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-FB8 / Cyclin-dependent kinase 2 / Cyclin-A2
Similarity search - Component
Biological speciesHomo sapiens (human)
Bos taurus (domestic cattle)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.99 Å
AuthorsWood, D.J. / Korolchuk, S. / Tatum, N.J. / Wang, L.Z. / Endicott, J.A. / Noble, M.E.M. / Martin, M.P.
Funding support United Kingdom, 2items
OrganizationGrant numberCountry
Medical Research Council (United Kingdom)MR/N009738/1 United Kingdom
Cancer Research UKC2115/A21421 United Kingdom
CitationJournal: Cell Chem Biol / Year: 2019
Title: Differences in the Conformational Energy Landscape of CDK1 and CDK2 Suggest a Mechanism for Achieving Selective CDK Inhibition.
Authors: Wood, D.J. / Korolchuk, S. / Tatum, N.J. / Wang, L.Z. / Endicott, J.A. / Noble, M.E.M. / Martin, M.P.
History
DepositionJun 19, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 5, 2018Provider: repository / Type: Initial release
Revision 1.1Jan 30, 2019Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year
Revision 1.2Jan 17, 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
Revision 1.3Nov 13, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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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
C: Cyclin-dependent kinase 2
D: Cyclin-A2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)131,1326
Polymers130,3904
Non-polymers7432
Water9,710539
1
A: Cyclin-dependent kinase 2
B: Cyclin-A2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)65,5593
Polymers65,1872
Non-polymers3711
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3500 Å2
ΔGint-17 kcal/mol
Surface area23240 Å2
MethodPISA
2
C: Cyclin-dependent kinase 2
D: Cyclin-A2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)65,5743
Polymers65,2022
Non-polymers3711
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3610 Å2
ΔGint-19 kcal/mol
Surface area23250 Å2
MethodPISA
Unit cell
Length a, b, c (Å)74.269, 133.224, 148.145
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: 34339.758 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CDK2, CDKN2 / Plasmid: pGEX6P1 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P24941, cyclin-dependent kinase
#2: Protein Cyclin-A2 / Cyclin-A


Mass: 30847.500 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Bos taurus (domestic cattle) / Gene: CCNA2 / Plasmid: pET21d / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P30274
#3: Protein Cyclin-dependent kinase 2 / Cell division protein kinase 2 / p33 protein kinase


Mass: 34354.770 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CDK2, CDKN2 / Plasmid: pGEX6P1 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P24941, cyclin-dependent kinase
#4: Chemical ChemComp-FB8 / 4-(2-methyl-3-propan-2-yl-imidazol-4-yl)-~{N}-(4-methylsulfonylphenyl)pyrimidin-2-amine


Mass: 371.457 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C18H21N5O2S / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 539 / Source method: isolated from a natural source / Formula: H2O
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: 2.81 Å3/Da / Density % sol: 56.23 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop
Details: PROTEIN AT 5MG PER ML. 0.6 TO 0.8M KCL, 0.9 TO 1.2M (NH402SO4, AND 100MM HEPES (PH 7.0), 0.5mM Inhibitor

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.987 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 25, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.987 Å / Relative weight: 1
ReflectionResolution: 1.99→99.26 Å / Num. obs: 99925 / % possible obs: 98.6 % / Redundancy: 6.5 % / Rmerge(I) obs: 0.1 / Net I/σ(I): 12.1
Reflection shellResolution: 1.99→2.02 Å / Redundancy: 4.6 % / Mean I/σ(I) obs: 1.2 / % possible all: 93.2

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Processing

Software
NameVersionClassification
REFMAC5.8.0158refinement
xia2data reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1H1S

1h1s


Resolution: 1.99→99.26 Å / Cor.coef. Fo:Fc: 0.955 / Cor.coef. Fo:Fc free: 0.931 / Cross valid method: THROUGHOUT / ESU R: 0.163 / ESU R Free: 0.151 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.23425 4909 4.9 %RANDOM
Rwork0.19652 ---
obs0.19836 95016 98.51 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 38.543 Å2
Baniso -1Baniso -2Baniso -3
1--0.38 Å2-0 Å2-0 Å2
2---0.23 Å20 Å2
3---0.61 Å2
Refinement stepCycle: 1 / Resolution: 1.99→99.26 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8908 0 52 539 9499
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0170.0199180
X-RAY DIFFRACTIONr_bond_other_d00.028702
X-RAY DIFFRACTIONr_angle_refined_deg1.7791.97412468
X-RAY DIFFRACTIONr_angle_other_deg3.5892.99420198
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.00251100
X-RAY DIFFRACTIONr_dihedral_angle_2_deg40.84723.97398
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.525151603
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.2351544
X-RAY DIFFRACTIONr_chiral_restr0.1130.21413
X-RAY DIFFRACTIONr_gen_planes_refined0.010.0219931
X-RAY DIFFRACTIONr_gen_planes_other0.0130.021813
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_it3.7573.6414421
X-RAY DIFFRACTIONr_mcbond_other3.7523.644420
X-RAY DIFFRACTIONr_mcangle_it5.5335.4285514
X-RAY DIFFRACTIONr_mcangle_other5.5335.435515
X-RAY DIFFRACTIONr_scbond_it4.8054.1234759
X-RAY DIFFRACTIONr_scbond_other4.8054.1224760
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other7.3696.0046955
X-RAY DIFFRACTIONr_long_range_B_refined9.88543.59910552
X-RAY DIFFRACTIONr_long_range_B_other9.89943.52710460
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.99→2.042 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.328 326 -
Rwork0.32 6603 -
obs--93.29 %

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