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- PDB-6gva: CDK2/cyclin A2 in complex with pyrazolo[4,3-d]pyrimidine inhibito... -

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Basic information

Entry
Database: PDB / ID: 6gva
TitleCDK2/cyclin A2 in complex with pyrazolo[4,3-d]pyrimidine inhibitor LGR4455
Components
  • Cyclin-A2
  • Cyclin-dependent kinase 2
KeywordsCELL CYCLE / cyclin-dependent kinase / 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-like ...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-like / Cyclin A; domain 1 / 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 / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
BROMIDE ION / Chem-FCQ / TRIETHYLENE GLYCOL / MONOTHIOGLYCEROL / Cyclin-A2 / Cyclin-dependent kinase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.15 Å
AuthorsSkerlova, J. / Rezacova, P.
Funding support Czech Republic, 2items
OrganizationGrant numberCountry
Ministry of Education (Czech Republic)programme NPU I: LO1304 Czech Republic
Grant Agency of the Czech RepublicGA17-14007S Czech Republic
CitationJournal: J.Med.Chem. / Year: 2019
Title: 3,5,7-Substituted Pyrazolo[4,3- d]pyrimidine Inhibitors of Cyclin-Dependent Kinases and Their Evaluation in Lymphoma Models.
Authors: Jorda, R. / Havlicek, L. / Sturc, A. / Tuskova, D. / Daumova, L. / Alam, M. / Skerlova, J. / Nekardova, M. / Perina, M. / Pospisil, T. / Siroka, J. / Urbanek, L. / Pachl, P. / Rezacova, P. / ...Authors: Jorda, R. / Havlicek, L. / Sturc, A. / Tuskova, D. / Daumova, L. / Alam, M. / Skerlova, J. / Nekardova, M. / Perina, M. / Pospisil, T. / Siroka, J. / Urbanek, L. / Pachl, P. / Rezacova, P. / Strnad, M. / Klener, P. / Krystof, V.
History
DepositionJun 20, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 1, 2019Provider: repository / Type: Initial release
Revision 1.1May 22, 2019Group: Data collection / Database references
Category: citation / citation_author ...citation / citation_author / database_PDB_rev / database_PDB_rev_record / pdbx_database_proc / pdbx_seq_map_depositor_info
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID / _pdbx_seq_map_depositor_info.one_letter_code_mod
Revision 1.2Jan 17, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,94211
Polymers63,7682
Non-polymers1,1749
Water2,882160
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4820 Å2
ΔGint-14 kcal/mol
Surface area23080 Å2
MethodPISA
Unit cell
Length a, b, c (Å)71.015, 112.642, 159.690
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221

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Components

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Protein , 2 types, 2 molecules AB

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


Mass: 34143.547 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 Cyclin-A2 / Cyclin-A / Cyclin A


Mass: 29624.297 Da / Num. of mol.: 1
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 , 8 types, 169 molecules

#3: Chemical ChemComp-FCQ / 5-(2-azanylethylsulfanyl)-3-propan-2-yl-~{N}-[(4-pyridin-2-ylphenyl)methyl]-2~{H}-pyrazolo[4,3-d]pyrimidin-7-amine


Mass: 419.546 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H25N7S / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#6: Chemical ChemComp-BR / BROMIDE ION / Bromide


Mass: 79.904 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Br
#7: Chemical ChemComp-PG4 / TETRAETHYLENE GLYCOL / Polyethylene glycol


Mass: 194.226 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H18O5 / Comment: precipitant*YM
#8: Chemical ChemComp-SGM / MONOTHIOGLYCEROL / 3-Mercaptopropane-1,2-diol


Mass: 108.159 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O2S
#9: Chemical ChemComp-PGE / TRIETHYLENE GLYCOL / Polyethylene glycol


Mass: 150.173 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H14O4
#10: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 160 / Source method: isolated from a natural source / Formula: H2O

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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: 2.57 Å3/Da / Density % sol: 52 % / Description: Thin diamond-shaped plates
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: 10% w/v PEG 20000, 20% v/v PEG MME 550, 0.03 M sodium fluoride, 0.03 M sodium bromide, 0.03 M sodium iodide, and 0.1 M bicine/Trizma base, pH 8.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.1 / Wavelength: 0.918 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jan 31, 2018 / Details: Sagitally bended Si111-crystal
RadiationMonochromator: Double crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.918 Å / Relative weight: 1
ReflectionResolution: 2.15→48 Å / Num. obs: 34773 / % possible obs: 98.3 % / Redundancy: 6.247 % / Biso Wilson estimate: 38.407 Å2 / CC1/2: 0.994 / Rmerge(I) obs: 0.195 / Rrim(I) all: 0.212 / Χ2: 0.936 / Net I/σ(I): 7.96 / Num. measured all: 217234
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsCC1/2Rrim(I) all% possible all
2.15-2.284.2951.4560.8650880.2981.66490.3
2.28-2.436.3561.051.6352770.6021.14499.7
2.43-2.636.8230.7712.4349630.7530.83499.9
2.63-2.886.5790.4743.8945690.8830.51599.9
2.88-3.226.8130.296.4141420.9620.314100
3.22-3.716.6190.13912.2936950.9910.15199.8
3.71-4.546.510.07920.1831260.9970.08599.9
4.54-6.396.6170.06822.5524670.9980.07499.8
6.39-485.9230.04429.9714460.9990.04999.2

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Processing

Software
NameVersionClassification
REFMAC5.8.0158refinement
XDSVersion Jun 1, 2017 BUILT=20170720data reduction
XDSVersion Jun 1, 2017 BUILT=20170720data scaling
MOLREPVers 11.4.06; 24.05.2016phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5LMK

5lmk


Resolution: 2.15→48 Å / Cor.coef. Fo:Fc: 0.961 / Cor.coef. Fo:Fc free: 0.928 / SU B: 8.018 / SU ML: 0.185 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.241 / ESU R Free: 0.198 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2403 1739 5 %RANDOM
Rwork0.1943 ---
obs0.1966 33033 98.31 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 110.39 Å2 / Biso mean: 39.552 Å2 / Biso min: 20.42 Å2
Baniso -1Baniso -2Baniso -3
1--0.03 Å2-0 Å20 Å2
2---0.06 Å2-0 Å2
3---0.1 Å2
Refinement stepCycle: final / Resolution: 2.15→48 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4402 0 73 160 4635
Biso mean--52.64 39.71 -
Num. residues----546
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.0194583
X-RAY DIFFRACTIONr_bond_other_d0.0020.024363
X-RAY DIFFRACTIONr_angle_refined_deg1.6191.9796202
X-RAY DIFFRACTIONr_angle_other_deg1.022.99310126
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.1045545
X-RAY DIFFRACTIONr_dihedral_angle_2_deg41.09823.949195
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.44415797
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.0211522
X-RAY DIFFRACTIONr_chiral_restr0.0920.2697
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0214914
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02906
LS refinement shellResolution: 2.147→2.203 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.364 109 -
Rwork0.37 2066 -
all-2175 -
obs--85.33 %

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