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- PDB-2c5v: Differential Binding Of Inhibitors To Active And Inactive Cdk2 Pr... -

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Basic information

Entry
Database: PDB / ID: 2c5v
TitleDifferential Binding Of Inhibitors To Active And Inactive Cdk2 Provides Insights For Drug Design
Components
  • ALA-ALA-ABA-ARG-SER-LEU-ILE-PFF-NH2
  • CELL DIVISION PROTEIN KINASE 2
  • CYCLIN A2
KeywordsCELL CYCLE / ATP-BINDING / CELL DIVISION / COMPLEX (KINASE-CYCLIN) / CYCIN A / CYCLIN / DRUG DESIGN / LIGAND EXCHANGE / KINASE / MITOSIS / NUCLEOTIDE-BINDING / PHOSPHORYLATION / SERINE/THREONINE-PROTEIN KINASE / TRANSFERASE / COMPLEX (TRANSFERASE-CYCLIN)
Function / homology
Function and homology information


: / cyclin A2-CDK1 complex / cellular response to luteinizing hormone stimulus / cell cycle G1/S 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 / response to glucagon / cellular response to cocaine ...: / cyclin A2-CDK1 complex / cellular response to luteinizing hormone stimulus / cell cycle G1/S 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 / response to glucagon / cellular response to cocaine / cyclin-dependent protein serine/threonine kinase regulator activity / positive regulation of DNA biosynthetic process / cellular response to insulin-like growth factor stimulus / cyclin A1-CDK2 complex / cyclin E2-CDK2 complex / cyclin E1-CDK2 complex / cochlea development / cyclin A2-CDK2 complex / positive regulation of DNA-templated DNA replication initiation / cyclin-dependent protein kinase activity / G2 Phase / 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) / microtubule organizing center / centriole replication / regulation of DNA replication / Regulation of APC/C activators between G1/S and early anaphase / telomere maintenance in response to DNA damage / centrosome duplication / Telomere Extension By Telomerase / G0 and Early G1 / Activation of the pre-replicative complex / animal organ regeneration / cyclin-dependent kinase / cyclin-dependent protein serine/threonine kinase activity / TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest / Regulation of MITF-M-dependent genes involved in cell cycle and proliferation / Cajal body / 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 / cyclin-dependent protein kinase holoenzyme complex / condensed chromosome / regulation of G2/M transition of mitotic cell cycle / cellular response to platelet-derived growth factor stimulus / mitotic G1 DNA damage checkpoint signaling / cellular response to nitric oxide / post-translational protein modification / cyclin binding / regulation of mitotic cell cycle / male germ cell nucleus / positive regulation of DNA replication / meiotic cell cycle / Cdc20:Phospho-APC/C mediated degradation of Cyclin A / cellular response to estradiol stimulus / potassium ion transport / DNA Damage/Telomere Stress Induced Senescence / Meiotic recombination / CDK-mediated phosphorylation and removal of Cdc6 / SCF(Skp2)-mediated degradation of p27/p21 / G1/S transition of mitotic cell cycle / Transcriptional regulation of granulopoiesis / Orc1 removal from chromatin / positive regulation of fibroblast proliferation / G2/M transition of mitotic cell cycle / Cyclin D associated events in G1 / cellular senescence / Regulation of TP53 Degradation / nuclear envelope / peptidyl-serine phosphorylation / Factors involved in megakaryocyte development and platelet production / Processing of DNA double-strand break ends / regulation of gene expression / Senescence-Associated Secretory Phenotype (SASP) / cellular response to hypoxia / Regulation of TP53 Activity through Phosphorylation / transcription regulator complex / Ras protein signal transduction / chromosome, telomeric region / DNA replication / endosome / Ub-specific processing proteases / protein phosphorylation / chromatin remodeling / protein domain specific binding / cell division / protein serine kinase activity / DNA repair / protein serine/threonine kinase activity / DNA-templated transcription / positive regulation of cell population proliferation / centrosome / protein kinase binding
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 / : / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / 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 / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-CK4 / Cyclin-A2 / Cyclin-dependent kinase 2
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
SYNTHETIC CONSTRUCT (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.9 Å
AuthorsKontopidis, G. / McInnes, C. / Pandalaneni, S.R. / McNae, I. / Gibson, D. / Mezna, M. / Thomas, M. / Wood, G. / Wang, S. / Walkinshaw, M.D. / Fischer, P.M.
CitationJournal: Chem.Biol. / Year: 2006
Title: Differential Binding of Inhibitors to Active and Inactive Cdk2 Provides Insights for Drug Design.
Authors: Kontopidis, G. / Mcinnes, C. / Pandalaneni, S.R. / Mcnae, I. / Gibson, D. / Mezna, M. / Thomas, M. / Wood, G. / Wang, S. / Walkinshaw, M.D. / Fischer, P.M.
History
DepositionNov 2, 2005Deposition site: PDBE / Processing site: PDBE
SupersessionMar 1, 2006ID: 1OKU
Revision 1.0Mar 1, 2006Provider: repository / Type: Initial release
Revision 1.1Feb 8, 2017Group: Derived calculations / Non-polymer description ...Derived calculations / Non-polymer description / Other / Source and taxonomy / Version format compliance
Revision 1.2Dec 13, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model / struct_conn / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _struct_conn.pdbx_leaving_atom_flag / _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: CELL DIVISION PROTEIN KINASE 2
B: CYCLIN A2
C: CELL DIVISION PROTEIN KINASE 2
D: CYCLIN A2
F: ALA-ALA-ABA-ARG-SER-LEU-ILE-PFF-NH2
H: ALA-ALA-ABA-ARG-SER-LEU-ILE-PFF-NH2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)129,9198
Polymers129,2186
Non-polymers7012
Water3,387188
1
A: CELL DIVISION PROTEIN KINASE 2
B: CYCLIN A2
F: ALA-ALA-ABA-ARG-SER-LEU-ILE-PFF-NH2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,9594
Polymers64,6093
Non-polymers3501
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
2
C: CELL DIVISION PROTEIN KINASE 2
D: CYCLIN A2
H: ALA-ALA-ABA-ARG-SER-LEU-ILE-PFF-NH2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,9594
Polymers64,6093
Non-polymers3501
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
Unit cell
Length a, b, c (Å)74.501, 114.549, 156.994
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21C
12B
22D

NCS domain segments:

Component-ID: 1 / End auth comp-ID: LEU / End label comp-ID: LEU / Refine code: 2

Dom-IDEns-IDBeg auth comp-IDBeg label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11METMETAA1 - 2961 - 296
21METMETCC1 - 2961 - 296
12VALVALBB175 - 4322 - 259
22VALVALDD175 - 4322 - 259

NCS ensembles :
ID
1
2

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Components

#1: Protein CELL DIVISION PROTEIN KINASE 2 / CYCLIN-DEPENDENT KINASE 2 / P33 PROTEIN KINASE


Mass: 33976.488 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Cell line (production host): SF9 / Production host: SPODOPTERA FRUGIPERDA (fall armyworm) / References: UniProt: P24941, EC: 2.7.1.37
#2: Protein CYCLIN A2 / CYCLIN A


Mass: 29753.410 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli) / References: UniProt: P20248
#3: Protein/peptide ALA-ALA-ABA-ARG-SER-LEU-ILE-PFF-NH2


Mass: 879.035 Da / Num. of mol.: 2 / Source method: obtained synthetically / Source: (synth.) SYNTHETIC CONSTRUCT (others)
#4: Chemical ChemComp-CK4 / 4-(2,4-DIMETHYL-1,3-THIAZOL-5-YL)-N-[4-(TRIFLUOROMETHYL)PHENYL]PYRIMIDIN-2-AMINE / 4-(2,4-DIMETHYL-THIAZOL-5-YL)-PYRIMIDIN-2-YL]-(4-TRIFLUOROMETHYL-PHENYL)-AMINE


Mass: 350.361 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C16H13F3N4S
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 188 / 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: 2.7 Å3/Da / Density % sol: 54 %
Crystal growpH: 7.8 / Details: 22% PEG 3350, 0.1M NA3-CIT, pH 7.80

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-2 / Wavelength: 0.933
DetectorType: ADSC CCD / Detector: CCD / Date: Nov 18, 2002 / Details: MIRRORS
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.933 Å / Relative weight: 1
ReflectionResolution: 2.9→12 Å / Num. obs: 24322 / % possible obs: 84.5 % / Redundancy: 13.8 % / Rmerge(I) obs: 0.1 / Net I/σ(I): 8.7
Reflection shellResolution: 2.9→2.97 Å / Rmerge(I) obs: 0.59 / Mean I/σ(I) obs: 1.4 / % possible all: 86.9

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Processing

Software
NameVersionClassification
REFMAC5.2.0005refinement
DENZOdata reduction
SCALEPACKdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1FIN

1fin


Resolution: 2.9→10 Å / Cor.coef. Fo:Fc: 0.949 / Cor.coef. Fo:Fc free: 0.859 / SU B: 18.751 / SU ML: 0.351 / Cross valid method: THROUGHOUT / ESU R Free: 0.545 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.282 1022 4.1 %RANDOM
Rwork0.171 ---
obs0.175 24033 84.5 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 35.76 Å2
Baniso -1Baniso -2Baniso -3
1--3.98 Å20 Å20 Å2
2--0.7 Å20 Å2
3---3.27 Å2
Refinement stepCycle: LAST / Resolution: 2.9→10 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9047 0 48 188 9283
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0229329
X-RAY DIFFRACTIONr_bond_other_d0.0010.028533
X-RAY DIFFRACTIONr_angle_refined_deg1.7751.99612671
X-RAY DIFFRACTIONr_angle_other_deg0.774319902
X-RAY DIFFRACTIONr_dihedral_angle_1_deg9.5251104
X-RAY DIFFRACTIONr_dihedral_angle_2_deg43.80723.924395
X-RAY DIFFRACTIONr_dihedral_angle_3_deg24.275151619
X-RAY DIFFRACTIONr_dihedral_angle_4_deg24.311545
X-RAY DIFFRACTIONr_chiral_restr0.0930.21432
X-RAY DIFFRACTIONr_gen_planes_refined0.0190.0210051
X-RAY DIFFRACTIONr_gen_planes_other0.0070.021828
X-RAY DIFFRACTIONr_nbd_refined0.3120.33085
X-RAY DIFFRACTIONr_nbd_other0.2950.39971
X-RAY DIFFRACTIONr_nbtor_refined0.2280.54785
X-RAY DIFFRACTIONr_nbtor_other0.1160.55295
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.2550.5630
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.360.329
X-RAY DIFFRACTIONr_symmetry_vdw_other0.4150.372
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.4990.58
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it4.1241.56938
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it5.28529047
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it7.88934564
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it11.2294.53624
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Dom-ID: 1 / Refine-ID: X-RAY DIFFRACTION

Ens-IDAuth asym-IDNumberTypeRms dev position (Å)Weight position
1A1740tight positional0.150.07
2B1523tight positional0.170.07
1A2898medium positional0.40.7
2B2513medium positional0.470.7
1A1740tight thermal0.60.9
2B1523tight thermal0.570.9
1A2898medium thermal1.592.3
2B2513medium thermal1.622.3
LS refinement shellResolution: 2.9→2.97 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rfree0.482 72
Rwork0.288 1708

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