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- PDB-7b7s: CDK2/cyclin A2 in complex with 3H-pyrazolo[4,3-f]quinoline-based ... -

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Basic information

Entry
Database: PDB / ID: 7b7s
TitleCDK2/cyclin A2 in complex with 3H-pyrazolo[4,3-f]quinoline-based derivative HSD1368
Components
  • Cyclin-A2
  • Cyclin-dependent kinase 2
KeywordsCELL CYCLE / cyclin-dependent kinase / FLT3 / acute myeloid leukemia / inhibition
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 / Defective binding of RB1 mutants to E2F1,(E2F2, E2F3) / regulation of DNA replication / 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 / cyclin-dependent kinase / Cajal body / 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 / response to organic substance / male germ cell nucleus / 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 / 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
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
NITRATE ION / MONOTHIOGLYCEROL / Chem-T1T / Cyclin-A2 / Cyclin-dependent kinase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.54 Å
AuthorsDjukic, S. / Skerlova, J. / Rezacova, P.
Funding support Czech Republic, 1items
OrganizationGrant numberCountry
European Regional Development FundCZ.02.1.01/0.0/0.0/16_019/0000729 Czech Republic
CitationJournal: J.Med.Chem. / Year: 2021
Title: 3 H -Pyrazolo[4,3- f ]quinoline-Based Kinase Inhibitors Inhibit the Proliferation of Acute Myeloid Leukemia Cells In Vivo.
Authors: Dayal, N. / Reznickova, E. / Hernandez, D.E. / Perina, M. / Torregrosa-Allen, S. / Elzey, B.D. / Skerlova, J. / Ajani, H. / Djukic, S. / Vojackova, V. / Lepsik, M. / Rezacova, P. / Krystof, ...Authors: Dayal, N. / Reznickova, E. / Hernandez, D.E. / Perina, M. / Torregrosa-Allen, S. / Elzey, B.D. / Skerlova, J. / Ajani, H. / Djukic, S. / Vojackova, V. / Lepsik, M. / Rezacova, P. / Krystof, V. / Jorda, R. / Sintim, H.O.
History
DepositionDec 11, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 4, 2021Provider: repository / Type: Initial release
Revision 1.1Aug 25, 2021Group: Database references / Category: citation / database_2
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.2Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id ..._struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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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)128,64710
Polymers127,5364
Non-polymers1,1116
Water1,38777
1
A: Cyclin-dependent kinase 2
B: Cyclin-A2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,3175
Polymers63,7682
Non-polymers5493
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2980 Å2
ΔGint-14 kcal/mol
Surface area24020 Å2
MethodPISA
2
C: Cyclin-dependent kinase 2
D: Cyclin-A2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,3295
Polymers63,7682
Non-polymers5623
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3510 Å2
ΔGint-26 kcal/mol
Surface area23790 Å2
MethodPISA
Unit cell
Length a, b, c (Å)70.077, 164.700, 73.411
Angle α, β, γ (deg.)90.000, 106.280, 90.000
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21C
12B
22D

NCS domain segments:

Component-ID: 0 / Refine code: 0

Dom-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11METMETVALVALAA1 - 2932 - 294
21METMETVALVALCC1 - 2932 - 294
12ASPASPLEULEUBB177 - 4303 - 256
22ASPASPLEULEUDD177 - 4303 - 256

NCS ensembles :
ID
1
2

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Components

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Protein , 2 types, 4 molecules ACBD

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


Mass: 34143.547 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 / Cyclin A


Mass: 29624.297 Da / Num. of mol.: 2
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

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Non-polymers , 5 types, 83 molecules

#3: Chemical ChemComp-T1T / 7-(3-(trifluoromethyl)-1H-pyrazol-4yl)-3,8,10,11-tetrahydropyrazolo[4,3-f]thiopyrano[3,4-c]quinoline 9-oxide


Mass: 391.370 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C17H12F3N5OS / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-NO3 / NITRATE ION / Nitrate


Mass: 62.005 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: NO3
#5: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#6: Chemical ChemComp-SGM / MONOTHIOGLYCEROL / 3-Mercaptopropane-1,2-diol


Mass: 108.159 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O2S
#7: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 77 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 3.19 Å3/Da / Density % sol: 61.42 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop
Details: 80% Morpheus condition 35 containing: 10% w/v PEG 4,000, 20% v/v glycerol, 0.03 M NaNO3, 0.03 M Na2HPO4, 0.03 M (NH4)2SO4, 0.1 M Tris/Bicine pH 8.5 and 20% of JCSG+ condition 59 containing: ...Details: 80% Morpheus condition 35 containing: 10% w/v PEG 4,000, 20% v/v glycerol, 0.03 M NaNO3, 0.03 M Na2HPO4, 0.03 M (NH4)2SO4, 0.1 M Tris/Bicine pH 8.5 and 20% of JCSG+ condition 59 containing: 14.4 % w/v PEG 8,000, 20% v/v Glycerol, 0.16 M calcium acetate, 0.08 M sodium cacodylate pH 6.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.1 / Wavelength: 0.918 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 3, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.918 Å / Relative weight: 1
ReflectionResolution: 2.54→47.1 Å / Num. obs: 43971 / % possible obs: 84 % / Redundancy: 5.502 % / Biso Wilson estimate: 35.409 Å2 / CC1/2: 0.968 / Rmerge(I) obs: 0.309 / Rrim(I) all: 0.342 / Χ2: 0.738 / Net I/σ(I): 5.35 / Num. measured all: 241913
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured obsNum. possibleNum. unique obsCC1/2Rrim(I) all% possible all
2.54-2.74.7621.429127782843458340.4681.59969.2
2.7-2.884.8871.0621.3828803788858940.621.18774.7
2.88-3.115.1760.8061.8931292733860460.760.89482.4
3.11-3.415.3180.5173.0330382681057130.8630.57283.9
3.41-3.815.3420.2925.3328379616553120.9520.32286.2
3.81-4.395.8530.1988.0629905546451090.980.21793.5
4.39-5.375.9920.1669.7926935460544950.9860.18297.6
5.37-7.557.0640.18210.1125035357335440.9880.19699.2
7.55-47.16.6210.0721.3813400206820240.9970.07697.9

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
XDSdata reduction
XSCALEdata scaling
MOLREPphasing
REFMAC5.8.0267refinement
PDB_EXTRACT3.27data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6gva

6gva


Resolution: 2.54→47.1 Å / Cor.coef. Fo:Fc: 0.895 / Cor.coef. Fo:Fc free: 0.853 / SU R Cruickshank DPI: 0.8009 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.801 / ESU R Free: 0.367 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2906 2129 4.8 %RANDOM
Rwork0.246 ---
obs0.2482 41850 84.07 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 139.28 Å2 / Biso mean: 37.521 Å2 / Biso min: 4.09 Å2
Baniso -1Baniso -2Baniso -3
1-6 Å20 Å22.37 Å2
2---3.52 Å20 Å2
3----3.3 Å2
Refinement stepCycle: final / Resolution: 2.54→47.1 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8729 0 73 77 8879
Biso mean--57.8 25.84 -
Num. residues----1083
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0139025
X-RAY DIFFRACTIONr_bond_other_d0.0340.0178722
X-RAY DIFFRACTIONr_angle_refined_deg1.6231.65312248
X-RAY DIFFRACTIONr_angle_other_deg2.2461.58120121
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.60651074
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.58722.494429
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.232151589
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.0181544
X-RAY DIFFRACTIONr_chiral_restr0.070.21154
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.029863
X-RAY DIFFRACTIONr_gen_planes_other0.0090.021979
Refine LS restraints NCS

Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Weight position: 0.05

Ens-IDDom-IDAuth asym-IDNumberRms dev position (Å)
11A89200.1
12C89200.1
21B82620.08
22D82620.08
LS refinement shellResolution: 2.544→2.61 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.376 120 -
Rwork0.33 2431 -
all-2551 -
obs--65.88 %

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