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- PDB-7qhl: Crystal structure of Cyclin-dependent kinase 2/cyclin A in comple... -

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Basic information

Entry
Database: PDB / ID: 7qhl
TitleCrystal structure of Cyclin-dependent kinase 2/cyclin A in complex with 3,5,7-Substituted pyrazolo[4,3-d]pyrimidine inhibitor 24
Components
  • Cyclin-A2
  • Cyclin-dependent kinase 2
KeywordsCELL CYCLE / cyclin-dependent kinase / inhibitor / pyrazolo[4 / 3-d]pyrimidine
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-D5P / DI(HYDROXYETHYL)ETHER / MONOTHIOGLYCEROL / Cyclin-A2 / Cyclin-dependent kinase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.7 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: J.Med.Chem. / Year: 2022
Title: 3,5,7-Substituted Pyrazolo[4,3- d ]Pyrimidine Inhibitors of Cyclin-Dependent Kinases and Cyclin K Degraders.
Authors: Jorda, R. / Havlicek, L. / Perina, M. / Vojackova, V. / Pospisil, T. / Djukic, S. / Skerlova, J. / Gruz, J. / Renesova, N. / Klener, P. / Rezacova, P. / Strnad, M. / Krystof, V.
History
DepositionDec 13, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 6, 2022Provider: repository / Type: Initial release
Revision 1.1Jul 27, 2022Group: 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
Revision 1.2Jan 31, 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)129,57620
Polymers127,5364
Non-polymers2,04116
Water17,366964
1
A: Cyclin-dependent kinase 2
B: Cyclin-A2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,84911
Polymers63,7682
Non-polymers1,0819
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4350 Å2
ΔGint-4 kcal/mol
Surface area23210 Å2
MethodPISA
2
C: Cyclin-dependent kinase 2
D: Cyclin-A2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,7279
Polymers63,7682
Non-polymers9597
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4380 Å2
ΔGint-7 kcal/mol
Surface area23530 Å2
MethodPISA
Unit cell
Length a, b, c (Å)69.890, 163.900, 73.170
Angle α, β, γ (deg.)90.000, 106.610, 90.000
Int Tables number4
Space group name H-MP1211

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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 , 6 types, 980 molecules

#3: Chemical ChemComp-D5P / 5-(2-amino-1-ethyl)thio-3-cyclobutyl-7-[4-(pyrazol-1-yl)benzyl]amino-1(2)H-pyrazolo[4,3-d]pyrimidine / 5-(2-azanylethylsulfanyl)-3-cyclobutyl-N-[(4-pyrazol-1-ylphenyl)methyl]-1H-pyrazolo[4,3-d]pyrimidin-7-amine


Mass: 420.534 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H24N8S / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


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


Mass: 62.068 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C2H6O2
#6: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER / Diethylene glycol


Mass: 106.120 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C4H10O3
#7: Chemical ChemComp-SGM / MONOTHIOGLYCEROL / 3-Mercaptopropane-1,2-diol


Mass: 108.159 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C3H8O2S
#8: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 964 / 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: 3.15 Å3/Da / Density % sol: 60.99 %
Crystal growTemperature: 291.15 K / Method: vapor diffusion, sitting drop / pH: 8.5
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%:20% w/v PEG 6000, 0.1 M Bicine, pH 9
PH range: 8.5-9

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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 PILATUS3 6M / Detector: PIXEL / Date: Mar 17, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 1.7→46.96 Å / Num. obs: 168531 / % possible obs: 97.3 % / Redundancy: 7.023 % / Biso Wilson estimate: 30.849 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.172 / Rrim(I) all: 0.185 / Χ2: 0.77 / Net I/σ(I): 10.77 / Num. measured all: 1183665
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
1.7-1.86.7781.9740.9718033027919266060.4822.13695.3
1.8-1.937.2351.2451.7318497726267255670.7551.3497.3
1.93-2.087.0930.7523.216936824420238770.90.81197.8
2.08-2.286.9190.4995.5515114822521218440.9530.53997
2.28-2.557.220.3419.1514425020351199800.9820.36798.2
2.55-2.946.9080.20614.4612154718024175940.9910.22297.6
2.94-3.597.2510.10625.3110921815201150630.9970.11499.1
3.59-5.076.8530.05238.857913411811115480.9980.05697.8
5.07-46.966.7720.0443.4943693662964520.9990.04397.3

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
REFMAC5.8.0267refinement
XDSdata reduction
XSCALEdata scaling
MOLREPphasing
PDB_EXTRACT3.27data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7B7S

7b7s


Resolution: 1.7→46.96 Å / Cor.coef. Fo:Fc: 0.964 / Cor.coef. Fo:Fc free: 0.95 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.097 / ESU R Free: 0.094 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2236 2100 1.2 %RANDOM
Rwork0.2001 ---
obs0.2004 166428 97.41 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 126.42 Å2 / Biso mean: 31.558 Å2 / Biso min: 9.19 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å2-0 Å2
2--0 Å20 Å2
3----0 Å2
Refinement stepCycle: final / Resolution: 1.7→46.96 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8761 0 135 969 9865
Biso mean--42.49 42.36 -
Num. residues----1086
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0170.0139225
X-RAY DIFFRACTIONr_bond_other_d0.0330.0178959
X-RAY DIFFRACTIONr_angle_refined_deg1.5711.64612511
X-RAY DIFFRACTIONr_angle_other_deg2.2621.57520698
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.89451111
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.75822.443438
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.619151619
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.4331545
X-RAY DIFFRACTIONr_chiral_restr0.0840.21177
X-RAY DIFFRACTIONr_gen_planes_refined0.010.0210055
X-RAY DIFFRACTIONr_gen_planes_other0.0130.022019
LS refinement shellResolution: 1.7→1.742 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.449 151 -
Rwork0.463 11992 -
obs--94.73 %

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