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- PDB-5cyi: CDK2/Cyclin A covalent complex with 6-(cyclohexylmethoxy)-N-(4-(v... -

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Basic information

Entry
Database: PDB / ID: 5cyi
TitleCDK2/Cyclin A covalent complex with 6-(cyclohexylmethoxy)-N-(4-(vinylsulfonyl)phenyl)-9H-purin-2-amine (NU6300)
Components
  • Cyclin-A2
  • Cyclin-dependent kinase 2
KeywordsTRANSFERASE / CDK2 Cyclin A covalent inhibitor vinylsulphone
Function / homology
Function and homology information


Phosphorylation of proteins involved in the G2/M transition by Cyclin A:Cdc2 complexes / cyclin A2-CDK1 complex / cell cycle G1/S phase transition / cellular response to luteinizing hormone stimulus / mitotic cell cycle 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 / cellular response to cocaine ...Phosphorylation of proteins involved in the G2/M transition by Cyclin A:Cdc2 complexes / cyclin A2-CDK1 complex / cell cycle G1/S phase transition / cellular response to luteinizing hormone stimulus / mitotic cell cycle 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 / cellular response to cocaine / response to glucagon / cyclin-dependent protein serine/threonine kinase regulator activity / cellular response to insulin-like growth factor stimulus / positive regulation of DNA biosynthetic process / cochlea development / cyclin A1-CDK2 complex / cyclin E2-CDK2 complex / cyclin E1-CDK2 complex / cellular response to platelet-derived growth factor stimulus / cyclin A2-CDK2 complex / positive regulation of DNA-templated DNA replication initiation / G2 Phase / cyclin-dependent protein kinase activity / 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 / regulation of DNA replication / Defective binding of RB1 mutants to E2F1,(E2F2, E2F3) / centriole replication / Regulation of APC/C activators between G1/S and early anaphase / centrosome duplication / Telomere Extension By Telomerase / G0 and Early G1 / Activation of the pre-replicative complex / cyclin-dependent protein kinase holoenzyme complex / cellular response to nitric oxide / Cajal body / cyclin-dependent kinase / animal organ regeneration / 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 / 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 / condensed chromosome / mitotic G1 DNA damage checkpoint signaling / regulation of mitotic cell cycle / regulation of G2/M transition of mitotic cell cycle / cyclin binding / post-translational protein modification / meiotic cell cycle / positive regulation of DNA replication / male germ cell nucleus / response to organic substance / cellular response to estradiol stimulus / Cdc20:Phospho-APC/C mediated degradation of Cyclin A / G1/S transition of mitotic cell cycle / potassium ion transport / DNA Damage/Telomere Stress Induced Senescence / CDK-mediated phosphorylation and removal of Cdc6 / SCF(Skp2)-mediated degradation of p27/p21 / Meiotic recombination / Orc1 removal from chromatin / Transcriptional regulation of granulopoiesis / Cyclin D associated events in G1 / G2/M transition of mitotic cell cycle / positive regulation of fibroblast proliferation / cellular senescence / Regulation of TP53 Degradation / nuclear envelope / Factors involved in megakaryocyte development and platelet production / Processing of DNA double-strand break ends / cellular response to hypoxia / Senescence-Associated Secretory Phenotype (SASP) / regulation of gene expression / peptidyl-serine phosphorylation / Ras protein signal transduction / Regulation of TP53 Activity through Phosphorylation / transcription regulator complex / DNA replication / chromosome, telomeric region / Ub-specific processing proteases / endosome / chromatin remodeling / cell division / protein domain specific binding / protein phosphorylation / DNA repair / protein serine kinase activity / protein serine/threonine kinase activity / centrosome / DNA-templated transcription / positive regulation of cell population proliferation / protein kinase binding / positive regulation of DNA-templated transcription
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-like ...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-like / Cyclin A; domain 1 / Cyclin, N-terminal / Cyclin, N-terminal domain / Cyclin-like / domain present in cyclins, TFIIB and Retinoblastoma / Cyclin-like superfamily / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; 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-55S / Cyclin-A2 / Cyclin-dependent kinase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsAnscombe, E. / Meschini, E. / Vidal, R.M. / Martin, M.P. / Staunton, D. / Geitmann, M. / Danielson, U.H. / Stanley, W.A. / Wang, L.Z. / Reuillon, T. ...Anscombe, E. / Meschini, E. / Vidal, R.M. / Martin, M.P. / Staunton, D. / Geitmann, M. / Danielson, U.H. / Stanley, W.A. / Wang, L.Z. / Reuillon, T. / Golding, B.T. / Cano, C. / Newell, D.R. / Noble, M.E.M. / Wedge, S.R. / Endicott, J.A. / Griffin, R.J.
Funding support United Kingdom, 3items
OrganizationGrant numberCountry
Medical Research Council (United Kingdom)G0901526 United Kingdom
Cancer Research UKC240/A15751 United Kingdom
European UnionFP6-PROKINASE United Kingdom
CitationJournal: Chem.Biol. / Year: 2015
Title: Identification and Characterization of an Irreversible Inhibitor of CDK2.
Authors: Anscombe, E. / Meschini, E. / Mora-Vidal, R. / Martin, M.P. / Staunton, D. / Geitmann, M. / Danielson, U.H. / Stanley, W.A. / Wang, L.Z. / Reuillon, T. / Golding, B.T. / Cano, C. / Newell, D. ...Authors: Anscombe, E. / Meschini, E. / Mora-Vidal, R. / Martin, M.P. / Staunton, D. / Geitmann, M. / Danielson, U.H. / Stanley, W.A. / Wang, L.Z. / Reuillon, T. / Golding, B.T. / Cano, C. / Newell, D.R. / Noble, M.E. / Wedge, S.R. / Endicott, J.A. / Griffin, R.J.
History
DepositionJul 30, 2015Deposition site: RCSB / Processing site: PDBE
Revision 1.0Sep 16, 2015Provider: repository / Type: Initial release
Revision 1.1Sep 30, 2015Group: Database references
Revision 1.2Aug 30, 2017Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Jan 10, 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

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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)129,5366
Polymers128,7054
Non-polymers8312
Water8,863492
1
A: Cyclin-dependent kinase 2
B: Cyclin-A2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,7683
Polymers64,3532
Non-polymers4161
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3200 Å2
ΔGint-15 kcal/mol
Surface area23280 Å2
MethodPISA
2
C: Cyclin-dependent kinase 2
D: Cyclin-A2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,7683
Polymers64,3532
Non-polymers4161
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3080 Å2
ΔGint-13 kcal/mol
Surface area23450 Å2
MethodPISA
Unit cell
Length a, b, c (Å)74.286, 135.289, 148.673
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: 34467.926 Da / Num. of mol.: 2
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: Protein Cyclin-A2 / Cyclin-A


Mass: 29884.605 Da / Num. of mol.: 2 / Fragment: UNP residues 174-432
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CCNA2, CCN1, CCNA / Production host: Escherichia coli (E. coli) / References: UniProt: P20248
#3: Chemical ChemComp-55S / 6-(cyclohexylmethoxy)-N-[4-(ethylsulfonyl)phenyl]-9H-purin-2-amine


Mass: 415.509 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H25N5O3S
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 492 / 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: 2.9 Å3/Da / Density % sol: 57.8 %
Crystal growTemperature: 277 K / Method: vapor diffusion
Details: Protein at 5 mg per ml. 0.6 to 0.8 M KCl, 0.9 to 1.2 M (NH4)2SO4, and 100 mM HEPES (pH 7.0)
PH range: pH 7.0

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04-1 / Wavelength: 0.92 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Sep 26, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.92 Å / Relative weight: 1
ReflectionResolution: 2→74.34 Å / Num. obs: 101717 / % possible obs: 99.9 % / Redundancy: 7.5 % / Rmerge(I) obs: 0.181 / Rsym value: 0.17 / Net I/σ(I): 8.9
Reflection shellResolution: 2→2.03 Å / Redundancy: 7.2 % / Rmerge(I) obs: 4.328 / Mean I/σ(I) obs: 0.5 / % possible all: 99.1

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Processing

Software
NameVersionClassification
REFMAC5.8.0123refinement
PDB_EXTRACT3.1data extraction
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1H1S
Resolution: 2→74.34 Å / Cor.coef. Fo:Fc: 0.951 / Cor.coef. Fo:Fc free: 0.936 / Occupancy max: 1 / Occupancy min: 0.5 / SU B: 7.238 / SU ML: 0.177 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.186 / ESU R Free: 0.163 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2548 4914 4.8 %RANDOM
Rwork0.2267 96721 --
obs0.2281 101635 99.85 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 158.67 Å2 / Biso mean: 52.6654 Å2 / Biso min: 17.97 Å2
Baniso -1Baniso -2Baniso -3
1--1.32 Å20 Å20 Å2
2--1.58 Å20 Å2
3----0.25 Å2
Refinement stepCycle: LAST / Resolution: 2→74.34 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8947 0 58 492 9497
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.0199254
X-RAY DIFFRACTIONr_angle_refined_deg1.7421.97112565
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.51451110
X-RAY DIFFRACTIONr_dihedral_angle_2_deg42.00123.939396
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.062151623
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.0321545
X-RAY DIFFRACTIONr_chiral_restr0.1060.21419
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.0216855
X-RAY DIFFRACTIONr_mcbond_it3.965.0084446
X-RAY DIFFRACTIONr_mcangle_it6.1227.4925554
X-RAY DIFFRACTIONr_scbond_it4.1875.464808
LS refinement shellResolution: 2→2.052 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.374 343 -
Rwork0.367 7041 -
all-7384 -
obs--99.25 %
Refinement TLS params.Method: refined / Origin x: 29.858 Å / Origin y: 59.545 Å / Origin z: 55.447 Å
111213212223313233
T0.0777 Å2-0.032 Å20.0069 Å2-0.1069 Å20.0233 Å2--0.04 Å2
L0.1523 °2-0.0093 °2-0.3167 °2-0.5902 °2-0.3065 °2--0.9344 °2
S0.1072 Å °-0.068 Å °0.0178 Å °0.0004 Å °-0.1448 Å °-0.1476 Å °-0.1962 Å °0.2572 Å °0.0376 Å °

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