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- PDB-2c6t: Crystal structure of the human CDK2 complexed with the triazolopy... -

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Basic information

Entry
Database: PDB / ID: 2c6t
TitleCrystal structure of the human CDK2 complexed with the triazolopyrimidine inhibitor
Components
  • CELL DIVISION PROTEIN KINASE 2
  • CYCLIN A2
KeywordsCELL CYCLE / SERINE/THREONINE PROTEIN KINASE / CDK2 / ATP-BINDING / MITOSIS / PHOSPHORYLATION / TRIAZOLOPYRIMIDINE INHIBITOR / COMPLEX (TRANSFERASE-CYCLIN2)
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 cocaine / cellular response to leptin stimulus / male pronucleus / female pronucleus ...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 cocaine / cellular response to leptin stimulus / male pronucleus / female pronucleus / 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 / regulation of DNA replication / Defective binding of RB1 mutants to E2F1,(E2F2, E2F3) / 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 / Cajal body / animal organ regeneration / cyclin-dependent kinase / cyclin-dependent protein serine/threonine kinase activity / Activation of ATR in response to replication stress / TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest / 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 G2/M transition of mitotic cell cycle / post-translational protein modification / response to organic substance / meiotic cell cycle / male germ cell nucleus / cyclin binding / 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 / protein domain specific binding / cell division / protein phosphorylation / DNA repair / protein serine kinase activity / protein serine/threonine kinase activity / DNA-templated transcription / centrosome / positive regulation of cell population proliferation / protein kinase binding / positive regulation of DNA-templated transcription / magnesium ion binding / negative regulation of transcription by RNA polymerase II
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 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; 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-DT5 / Cyclin-A2 / Cyclin-dependent kinase 2
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.61 Å
AuthorsRichardson, C.M. / Dokurno, P. / Murray, J.B. / Surgenor, A.E.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2006
Title: Triazolo[1,5-A]Pyrimidines as Novel Cdk2 Inhibitors: Protein Structure-Guided Design and Sar.
Authors: Richardson, C.M. / Williamson, D.S. / Parratt, M.J. / Borgognoni, J. / Cansfield, A.D. / Dokurno, P. / Francis, G.L. / Howes, R. / Moore, J.D. / Murray, J.B. / Robertson, A. / Surgenor, A.E. / Torrance, C.J.
History
DepositionNov 11, 2005Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 7, 2005Provider: repository / Type: Initial release
Revision 1.1May 8, 2011Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Mar 6, 2019Group: Data collection / Derived calculations ...Data collection / Derived calculations / Experimental preparation / Other
Category: exptl_crystal_grow / pdbx_database_proc ...exptl_crystal_grow / pdbx_database_proc / pdbx_database_status / pdbx_seq_map_depositor_info / struct_conn
Item: _exptl_crystal_grow.method / _pdbx_database_status.recvd_author_approval ..._exptl_crystal_grow.method / _pdbx_database_status.recvd_author_approval / _pdbx_seq_map_depositor_info.one_letter_code_mod / _struct_conn.pdbx_leaving_atom_flag
Revision 1.4Apr 3, 2019Group: Data collection / Experimental preparation / Category: exptl_crystal_grow / pdbx_seq_map_depositor_info
Item: _exptl_crystal_grow.temp / _pdbx_seq_map_depositor_info.one_letter_code_mod
Revision 1.5Dec 13, 2023Group: Data collection / Database references ...Data collection / Database references / 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
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)128,1386
Polymers127,3624
Non-polymers7772
Water6,431357
1
A: CELL DIVISION PROTEIN KINASE 2
B: CYCLIN A2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,0693
Polymers63,6812
Non-polymers3881
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
2
C: CELL DIVISION PROTEIN KINASE 2
D: CYCLIN A2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,0693
Polymers63,6812
Non-polymers3881
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
Unit cell
Length a, b, c (Å)160.418, 161.345, 66.221
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11B
21D

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Components

#1: Protein CELL DIVISION PROTEIN KINASE 2 / / P33 PROTEIN KINASE


Mass: 34056.469 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: THR160 PHOSPHORYLATED / Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21 / References: UniProt: P24941, EC: 2.7.1.37
#2: Protein CYCLIN A2 / / CYCLIN-A


Mass: 29624.297 Da / Num. of mol.: 2 / Fragment: RESIDUES 175-432
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21 / References: UniProt: P20248
#3: Chemical ChemComp-DT5 / 4-{[5-(CYCLOHEXYLOXY)[1,2,4]TRIAZOLO[1,5-A]PYRIMIDIN-7-YL]AMINO}BENZENESULFONAMIDE


Mass: 388.444 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C17H20N6O3S
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 357 / 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: 3.3 Å3/Da / Density % sol: 63 %
Crystal growTemperature: 277 K / Method: vapor diffusion / pH: 7
Details: VAPOUR DIFFUSION AT 4 DEG C, 0.1 M HEPES PH 7.0, 1M LITHIUM SULPHATE

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-4 / Wavelength: 0.9393
DetectorType: ADSC CCD / Detector: CCD / Date: Jun 19, 2003
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9393 Å / Relative weight: 1
ReflectionResolution: 2.6→20 Å / Num. obs: 50329 / % possible obs: 95 % / Redundancy: 2.8 % / Rmerge(I) obs: 0.18 / Net I/σ(I): 5
Reflection shellResolution: 2.6→2.69 Å / Redundancy: 2.7 % / Rmerge(I) obs: 0.52 / Mean I/σ(I) obs: 1.99 / % possible all: 97

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Processing

Software
NameVersionClassification
REFMAC5.1.24refinement
DENZOdata reduction
SCALEPACKdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1GY3
Resolution: 2.61→15 Å / Cor.coef. Fo:Fc: 0.915 / Cor.coef. Fo:Fc free: 0.86 / SU B: 10.432 / SU ML: 0.219 / Cross valid method: THROUGHOUT / ESU R: 0.515 / ESU R Free: 0.308 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.257 2557 5.1 %RANDOM
Rwork0.2 ---
obs0.202 47621 94.7 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 28.44 Å2
Baniso -1Baniso -2Baniso -3
1-0.13 Å20 Å20 Å2
2---0.02 Å20 Å2
3----0.11 Å2
Refinement stepCycle: LAST / Resolution: 2.61→15 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8930 0 54 357 9341
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.0229218
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.4451.96312524
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.0851104
X-RAY DIFFRACTIONr_dihedral_angle_2_deg
X-RAY DIFFRACTIONr_dihedral_angle_3_deg
X-RAY DIFFRACTIONr_dihedral_angle_4_deg
X-RAY DIFFRACTIONr_chiral_restr0.1010.21410
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.026854
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.2280.24386
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.160.2422
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1830.244
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1840.27
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.7071.55556
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.3929034
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.94833662
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it3.3764.53490
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 / Auth asym-ID: B / Ens-ID: 1 / Number: 2084 / Refine-ID: X-RAY DIFFRACTION

TypeRms dev position (Å)Weight position
tight positional0.050.05
tight thermal0.120.5
LS refinement shellResolution: 2.61→2.67 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rfree0.308 187
Rwork0.248 3242

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