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- PDB-8b54: CDK2/cyclin A2 in complex with pyrazolo[4,3-d]pyrimidine inhibito... -

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Basic information

Entry
Database: PDB / ID: 8b54
TitleCDK2/cyclin A2 in complex with pyrazolo[4,3-d]pyrimidine inhibitor LGR6768
Components
  • Cyclin-A2
  • Cyclin-dependent kinase 2
KeywordsCELL CYCLE / cyclin-dependent kinase 2 / cyclin A2 / cancer
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
Chem-P2V / Cyclin-A2 / Cyclin-dependent kinase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.6 Å
AuthorsDjukic, S. / Skerlova, J. / Rezacova, P.
Funding supportEuropean Union, 1items
OrganizationGrant numberCountry
European Regional Development FundCZ.02.1.01/0.0/0.0/16_019/0000729European Union
CitationJournal: Biomed Pharmacother / Year: 2023
Title: Characterization of new highly selective pyrazolo[4,3-d]pyrimidine inhibitor of CDK7.
Authors: Kovalova, M. / Havlicek, L. / Djukic, S. / Skerlova, J. / Perina, M. / Pospisil, T. / Reznickova, E. / Rezacova, P. / Jorda, R. / Krystof, V.
History
DepositionSep 21, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 29, 2023Provider: repository / Type: Initial release
Revision 1.1Feb 7, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)128,94512
Polymers127,5364
Non-polymers1,4108
Water5,657314
1
A: Cyclin-dependent kinase 2
B: Cyclin-A2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,4736
Polymers63,7682
Non-polymers7054
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3580 Å2
ΔGint-14 kcal/mol
Surface area23040 Å2
MethodPISA
2
C: Cyclin-dependent kinase 2
D: Cyclin-A2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,4736
Polymers63,7682
Non-polymers7054
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3550 Å2
ΔGint-12 kcal/mol
Surface area23030 Å2
MethodPISA
Unit cell
Length a, b, c (Å)73.023, 134.978, 163.963
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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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 BL21(DE3) (bacteria) / 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 BL21(DE3) (bacteria) / References: UniProt: P20248

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Non-polymers , 4 types, 322 molecules

#3: Chemical ChemComp-P2V / ~{N}-[(2-phenylphenyl)methyl]-5-piperidin-4-ylsulfanyl-3-propan-2-yl-2~{H}-pyrazolo[4,3-d]pyrimidin-7-amine


Mass: 458.622 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C26H30N6S / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C3H8O3
#5: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 314 / 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: 3.17 Å3/Da / Density % sol: 61.17 %
Crystal growTemperature: 291.15 K / Method: vapor diffusion, sitting drop
Details: 70%: 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 30%:0.8 M sodium phosphate monobasic monohydrate, 0.8 M potassium phosphate ...Details: 70%: 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 30%:0.8 M sodium phosphate monobasic monohydrate, 0.8 M potassium phosphate monobasic, 0.1 M Sodium HEPES, pH7.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.1 / Wavelength: 0.9184 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Oct 22, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 2.6→50 Å / Num. obs: 50620 / % possible obs: 99.9 % / Redundancy: 13.6 % / Biso Wilson estimate: 39.44 Å2 / CC1/2: 0.988 / Net I/σ(I): 5.42
Reflection shellResolution: 2.6→2.76 Å / Mean I/σ(I) obs: 1.01 / Num. unique obs: 8027 / CC1/2: 0.717

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Processing

Software
NameVersionClassification
REFMAC5.8.0232refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
XSCALEdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6GVA

6gva


Resolution: 2.6→49.56 Å / Cor.coef. Fo:Fc: 0.947 / Cor.coef. Fo:Fc free: 0.914 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.534 / ESU R Free: 0.328 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2874 1460 2.9 %RANDOM
Rwork0.2328 ---
obs0.2344 49156 99.9 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 141.78 Å2 / Biso mean: 39.612 Å2 / Biso min: 0.67 Å2
Baniso -1Baniso -2Baniso -3
1-0.07 Å20 Å20 Å2
2---0.12 Å20 Å2
3---0.05 Å2
Refinement stepCycle: final / Resolution: 2.6→49.56 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8828 0 98 314 9240
Biso mean--48.98 30.8 -
Num. residues----1095
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0139167
X-RAY DIFFRACTIONr_bond_other_d0.0340.0178711
X-RAY DIFFRACTIONr_angle_refined_deg1.5961.65612439
X-RAY DIFFRACTIONr_angle_other_deg2.2371.58120226
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.03351093
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.72622.506435
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.355151601
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.9421544
X-RAY DIFFRACTIONr_chiral_restr0.0710.21165
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.029936
X-RAY DIFFRACTIONr_gen_planes_other0.010.021866
LS refinement shellResolution: 2.6→2.667 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.398 105 -
Rwork0.403 3539 -
all-3644 -
obs--99.89 %

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