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- PDB-8uv0: Discovery of (4-Pyrazolyl)-2-Aminopyrimidines as Potent and Selec... -

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Basic information

Entry
Database: PDB / ID: 8uv0
TitleDiscovery of (4-Pyrazolyl)-2-Aminopyrimidines as Potent and Selective Inhibitors of Cyclin-Dependent Kinase 2
ComponentsCyclin-dependent kinase 2
KeywordsTRANSFERASE/INHIBITOR / CDK2 / serine/threonine kinase / cell cycle regulation / aminopyrimidine / inhibitor / 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 / 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 ...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 / 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 / Activation of the pre-replicative complex / cellular response to nitric oxide / cyclin-dependent protein kinase holoenzyme 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 / Cyclin E associated events during G1/S transition / Cyclin A/B1/B2 associated events during G2/M transition / Cajal body / 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 / 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 / G1/S transition of mitotic cell cycle / Transcriptional regulation of granulopoiesis / G2/M transition of mitotic cell cycle / 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 / Senescence-Associated Secretory Phenotype (SASP) / regulation of gene expression / peptidyl-serine phosphorylation / DNA replication / Regulation of TP53 Activity through Phosphorylation / transcription regulator complex / Ras protein signal transduction / chromosome, telomeric region / endosome / chromatin remodeling / protein domain specific binding / cell division / protein phosphorylation / DNA repair / protein serine kinase activity / protein serine/threonine kinase activity / DNA-templated transcription / centrosome / positive regulation of cell population proliferation / positive regulation of DNA-templated transcription / negative regulation of transcription by RNA polymerase II / magnesium ion binding / signal transduction / nucleoplasm / ATP binding / nucleus / cytoplasm / cytosol
Similarity search - Function
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
: / Cyclin-dependent kinase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.55 Å
AuthorsDeller, M.C. / Epling, L.B.
Funding support United States, 1items
OrganizationGrant numberCountry
Other private United States
CitationJournal: J.Med.Chem. / Year: 2024
Title: Discovery of (4-Pyrazolyl)-2-aminopyrimidines as Potent and Selective Inhibitors of Cyclin-Dependent Kinase 2.
Authors: Hummel, J.R. / Xiao, K.J. / Yang, J.C. / Epling, L.B. / Mukai, K. / Ye, Q. / Xu, M. / Qian, D. / Huo, L. / Weber, M. / Roman, V. / Lo, Y. / Drake, K. / Stump, K. / Covington, M. / ...Authors: Hummel, J.R. / Xiao, K.J. / Yang, J.C. / Epling, L.B. / Mukai, K. / Ye, Q. / Xu, M. / Qian, D. / Huo, L. / Weber, M. / Roman, V. / Lo, Y. / Drake, K. / Stump, K. / Covington, M. / Kapilashrami, K. / Zhang, G. / Ye, M. / Diamond, S. / Yeleswaram, S. / Macarron, R. / Deller, M.C. / Wee, S. / Kim, S. / Wang, X. / Wu, L. / Yao, W.
History
DepositionNov 2, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 14, 2024Provider: repository / Type: Initial release
Revision 1.1Mar 6, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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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)34,3342
Polymers33,8451
Non-polymers4891
Water2,198122
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)53.663, 72.009, 71.913
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: 33845.297 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 BL21(DE3) (bacteria) / Variant (production host): R3 / References: UniProt: P24941, cyclin-dependent kinase
#2: Chemical ChemComp-XKU / 1-{(4M)-4-[2-{[1-(cyclopropanesulfonyl)piperidin-4-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl]-1H-pyrazol-1-yl}-2-methylpropan-2-ol


Mass: 488.527 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H27F3N6O3S / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 122 / 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: 2.04 Å3/Da / Density % sol: 39.84 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: 0.1 M Tris pH 8.5, 16% PEG 2000 MME, 0.2 M trimethylamine N-oxide

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: MAX IV / Beamline: BioMAX / Wavelength: 0.9763 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jul 8, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9763 Å / Relative weight: 1
ReflectionResolution: 1.4→43.01 Å / Num. obs: 55105 / % possible obs: 99.8 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 13.4 % / Biso Wilson estimate: 21.52 Å2 / CC1/2: 0.997 / Rmerge(I) obs: 0.07 / Rpim(I) all: 0.02 / Net I/σ(I): 16.2
Reflection shellResolution: 1.4→1.43 Å / Redundancy: 13.5 % / Rmerge(I) obs: 1.54 / Mean I/σ(I) obs: 2.2 / Num. unique obs: 2666 / CC1/2: 0.892 / Rpim(I) all: 0.43 / % possible all: 99.5

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Processing

Software
NameVersionClassification
REFMAC5.8.0352refinement
XDSdata reduction
STARANISOdata scaling
DIMPLEphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.55→43.004 Å / Cor.coef. Fo:Fc: 0.97 / Cor.coef. Fo:Fc free: 0.957 / WRfactor Rfree: 0.224 / WRfactor Rwork: 0.162 / SU B: 3.248 / SU ML: 0.053 / Average fsc free: 0.9727 / Average fsc work: 0.988 / Cross valid method: FREE R-VALUE / ESU R: 0.086 / ESU R Free: 0.078
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2034 2096 5.095 %
Rwork0.155 39044 -
all0.158 --
obs-41140 99.917 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 27.907 Å2
Baniso -1Baniso -2Baniso -3
1--0.608 Å2-0 Å2-0 Å2
2---0.603 Å20 Å2
3---1.211 Å2
Refinement stepCycle: LAST / Resolution: 1.55→43.004 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2132 0 33 122 2287
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0122226
X-RAY DIFFRACTIONr_bond_other_d0.0030.0162057
X-RAY DIFFRACTIONr_angle_refined_deg1.8631.6463042
X-RAY DIFFRACTIONr_angle_other_deg0.7391.5814759
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.2375277
X-RAY DIFFRACTIONr_dihedral_angle_2_deg13.29659
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.40210339
X-RAY DIFFRACTIONr_dihedral_angle_6_deg17.0431083
X-RAY DIFFRACTIONr_chiral_restr0.0990.2346
X-RAY DIFFRACTIONr_gen_planes_refined0.0110.022528
X-RAY DIFFRACTIONr_gen_planes_other0.0030.02440
X-RAY DIFFRACTIONr_nbd_refined0.2240.2379
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1630.21834
X-RAY DIFFRACTIONr_nbtor_refined0.1750.21107
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0730.21180
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1190.287
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.1630.210
X-RAY DIFFRACTIONr_nbd_other0.1390.241
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.1610.28
X-RAY DIFFRACTIONr_mcbond_it3.9742.2221114
X-RAY DIFFRACTIONr_mcbond_other3.9742.2221114
X-RAY DIFFRACTIONr_mcangle_it4.5863.3331386
X-RAY DIFFRACTIONr_mcangle_other4.5853.3331387
X-RAY DIFFRACTIONr_scbond_it4.5742.5231112
X-RAY DIFFRACTIONr_scbond_other4.5722.5231113
X-RAY DIFFRACTIONr_scangle_it5.213.6811652
X-RAY DIFFRACTIONr_scangle_other5.2083.6811653
X-RAY DIFFRACTIONr_lrange_it5.0831.6712386
X-RAY DIFFRACTIONr_lrange_other5.08130.8892370
X-RAY DIFFRACTIONr_rigid_bond_restr6.80434283
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 20

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRfactor allNum. reflection allFsc freeFsc work% reflection obs (%)WRfactor Rwork
1.55-1.590.2361770.16128110.16529920.960.98199.86630.131
1.59-1.6340.2311650.1427790.14529470.9720.98799.89820.116
1.634-1.6810.2071400.11926850.12428290.9740.99199.85860.099
1.681-1.7330.2521510.12226080.12827600.9620.99199.96380.104
1.733-1.7890.2171360.11625490.12126850.9740.9921000.102
1.789-1.8520.1841300.11124870.11526170.9790.9921000.101
1.852-1.9220.24870.10924070.11324950.970.99299.95990.102
1.922-20.191180.11523130.11924310.9780.9921000.113
2-2.0890.2211000.12322100.12723100.9710.9911000.123
2.089-2.1910.1811110.1221140.12322260.980.99299.95510.122
2.191-2.3090.2121070.13120060.13621130.9740.991000.139
2.309-2.4480.1781380.13718930.1420310.9810.9891000.151
2.448-2.6170.197860.13417860.13718720.9780.9891000.152
2.617-2.8260.205700.15617220.15817920.9730.9851000.18
2.826-3.0940.171850.1615530.16116380.9790.9841000.189
3.094-3.4570.212880.16414100.16714990.9690.98499.93330.2
3.457-3.9870.166620.16612560.16613180.9850.9841000.204
3.987-4.8730.209600.15710900.15911510.9710.98599.91310.215
4.873-6.8480.216480.2118540.2119030.9730.97699.88930.295
6.848-43.0040.27360.2765010.2765510.9480.95697.45920.39
Refinement TLS params.Method: refined / Origin x: 10.8571 Å / Origin y: -4.2209 Å / Origin z: -12.8274 Å
111213212223313233
T0.0126 Å2-0.0145 Å20.0051 Å2-0.0294 Å2-0.002 Å2--0.0111 Å2
L0.7847 °2-0.1156 °20.2744 °2-2.0647 °2-0.2033 °2--0.617 °2
S0.0362 Å °-0.018 Å °0.0627 Å °0.0357 Å °-0.0458 Å °-0.0996 Å °-0.0564 Å °0.1113 Å °0.0096 Å °
Refinement TLS groupSelection: ALL

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