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- PDB-8h6p: Complex structure of CDK2/Cyclin E1 and a potent, selective macro... -

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Basic information

Entry
Database: PDB / ID: 8h6p
TitleComplex structure of CDK2/Cyclin E1 and a potent, selective macrocyclic inhibitor
Components
  • Cyclin-dependent kinase 2
  • G1/S-specific cyclin-E1
KeywordsCELL CYCLE / Inhibitor / Complex / Selective / Anti-tumor
Function / homology
Function and homology information


positive regulation of mesenchymal stem cell proliferation / homologous chromosome pairing at meiosis / RHOBTB3 ATPase cycle / cyclin-dependent protein serine/threonine kinase regulator activity / G1/S-Specific Transcription / cyclin A1-CDK2 complex / cyclin E2-CDK2 complex / cyclin E1-CDK2 complex / cyclin A2-CDK2 complex / positive regulation of DNA-templated DNA replication initiation ...positive regulation of mesenchymal stem cell proliferation / homologous chromosome pairing at meiosis / RHOBTB3 ATPase cycle / cyclin-dependent protein serine/threonine kinase regulator activity / G1/S-Specific Transcription / 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 / 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 / Association of TriC/CCT with target proteins during biosynthesis / 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 / centrosome duplication / Telomere Extension By Telomerase / G0 and Early G1 / DNA replication initiation / Activation of the pre-replicative complex / cyclin-dependent protein kinase holoenzyme complex / cellular response to nitric oxide / cyclin-dependent kinase / Cajal body / 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 / telomere maintenance / cyclin binding / post-translational protein modification / meiotic cell cycle / positive regulation of DNA replication / response to organic substance / male germ cell nucleus / 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 / Wnt signaling pathway / Meiotic recombination / Orc1 removal from chromatin / Transcriptional regulation of granulopoiesis / Cyclin D associated events in G1 / regulation of protein localization / G2/M transition of mitotic cell cycle / cellular senescence / Regulation of TP53 Degradation / nuclear envelope / Factors involved in megakaryocyte development and platelet production / kinase activity / Processing of DNA double-strand break ends / 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 / regulation of cell cycle / endosome / chromatin remodeling / cell division / protein domain specific binding / protein phosphorylation / protein serine kinase activity / DNA repair / protein serine/threonine kinase activity / centrosome / DNA-templated transcription / positive regulation of cell population proliferation / protein kinase binding / 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
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, 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
Chem-WZU / G1/S-specific cyclin-E1 / Cyclin-dependent kinase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.44 Å
AuthorsRen, X.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Acs Med.Chem.Lett. / Year: 2023
Title: Accelerated Discovery of Macrocyclic CDK2 Inhibitor QR-6401 by Generative Models and Structure-Based Drug Design.
Authors: Yu, Y. / Huang, J. / He, H. / Han, J. / Ye, G. / Xu, T. / Sun, X. / Chen, X. / Ren, X. / Li, C. / Li, H. / Huang, W. / Liu, Y. / Wang, X. / Gao, Y. / Cheng, N. / Guo, N. / Chen, X. / Feng, J. ...Authors: Yu, Y. / Huang, J. / He, H. / Han, J. / Ye, G. / Xu, T. / Sun, X. / Chen, X. / Ren, X. / Li, C. / Li, H. / Huang, W. / Liu, Y. / Wang, X. / Gao, Y. / Cheng, N. / Guo, N. / Chen, X. / Feng, J. / Hua, Y. / Liu, C. / Zhu, G. / Xie, Z. / Yao, L. / Zhong, W. / Chen, X. / Liu, W. / Li, H.
History
DepositionOct 18, 2022Deposition site: PDBJ / Processing site: RCSB
Revision 1.0Feb 22, 2023Provider: repository / Type: Initial release
Revision 1.1Mar 29, 2023Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title

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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: G1/S-specific cyclin-E1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)66,0673
Polymers65,6962
Non-polymers3701
Water90150
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3610 Å2
ΔGint-20 kcal/mol
Surface area24190 Å2
MethodPISA
Unit cell
Length a, b, c (Å)101.588, 101.588, 152.425
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number92
Space group name H-MP41212

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Components

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


Mass: 34040.426 Da / Num. of mol.: 1
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 G1/S-specific cyclin-E1


Mass: 31655.822 Da / Num. of mol.: 1 / Fragment: Residues 103-373
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CCNE1, CCNE / Production host: Escherichia coli (E. coli) / References: UniProt: P24864
#3: Chemical ChemComp-WZU / (7S,10R)-11-oxa-2,4,5,13,17,23-hexaazatetracyclo[17.3.1.1~3,6~.1~7,10~]pentacosa-1(23),3(25),5,19,21-pentaene-12,18-dione


Mass: 370.406 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H22N6O3
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 50 / 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: 3 Å3/Da / Density % sol: 59.09 %
Crystal growTemperature: 291.15 K / Method: vapor diffusion, hanging drop / Details: 0.2 M sodium citrate pH 6.5, 10% PEG3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL02U1 / Wavelength: 1 Å
DetectorType: DECTRIS EIGER2 S 9M / Detector: PIXEL / Date: Dec 15, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.44→45.43 Å / Num. obs: 30394 / % possible obs: 99.82 % / Redundancy: 2 % / CC1/2: 1 / CC star: 1 / Rmerge(I) obs: 0.01171 / Rpim(I) all: 0.01171 / Rrim(I) all: 0.01657 / Net I/σ(I): 19.08
Reflection shellResolution: 2.44→2.527 Å / Rmerge(I) obs: 0.3031 / Mean I/σ(I) obs: 2.34 / Num. unique obs: 2967 / CC1/2: 0.832 / CC star: 0.953 / Rpim(I) all: 0.3031 / Rrim(I) all: 0.4286

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Processing

Software
NameVersionClassification
SCALEPACKdata scaling
PHENIXv1.13-2998refinement
PDB_EXTRACT3.27data extraction
HKL-2000data reduction
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1W98

1w98


Resolution: 2.44→45.43 Å / Cor.coef. Fo:Fc: 0.952 / Cor.coef. Fo:Fc free: 0.917 / SU B: 12.673 / SU ML: 0.279 / Cross valid method: THROUGHOUT / ESU R: 0.372 / ESU R Free: 0.297 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2924 1574 5.2 %RANDOM
Rwork0.2211 ---
obs0.22207 30394 99.82 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 78.41 Å2
Baniso -1Baniso -2Baniso -3
1-1.5 Å2-0 Å2-0 Å2
2--1.5 Å2-0 Å2
3----2.99 Å2
Refinement stepCycle: 1 / Resolution: 2.44→45.43 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4623 0 27 50 4700
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0134772
X-RAY DIFFRACTIONr_bond_other_d0.0010.0174513
X-RAY DIFFRACTIONr_angle_refined_deg1.6261.6456480
X-RAY DIFFRACTIONr_angle_other_deg1.2471.57710467
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.6035567
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.78122.415236
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.81315837
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.1041525
X-RAY DIFFRACTIONr_chiral_restr0.0730.2606
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.025190
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02995
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_it7.2957.5272274
X-RAY DIFFRACTIONr_mcbond_other7.2847.5262273
X-RAY DIFFRACTIONr_mcangle_it10.311.2772839
X-RAY DIFFRACTIONr_mcangle_other10.29911.2792840
X-RAY DIFFRACTIONr_scbond_it7.2658.0652497
X-RAY DIFFRACTIONr_scbond_other7.2648.0642498
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other10.45411.8843642
X-RAY DIFFRACTIONr_long_range_B_refined13.74288.2325462
X-RAY DIFFRACTIONr_long_range_B_other13.74688.2355458
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.44→2.503 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.352 114 -
Rwork0.323 2085 -
obs--99.64 %

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