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- PDB-2iw8: STRUCTURE OF HUMAN THR160-PHOSPHO CDK2-CYCLIN A F82H-L83V-H84D MU... -

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Basic information

Entry
Database: PDB / ID: 2iw8
TitleSTRUCTURE OF HUMAN THR160-PHOSPHO CDK2-CYCLIN A F82H-L83V-H84D MUTANT WITH AN O6-CYCLOHEXYLMETHYLGUANINE INHIBITOR
Components
  • CELL DIVISION PROTEIN KINASE 2
  • CYCLIN-A2
KeywordsCELL CYCLE / PHOSPHORYLATION / NUCLEOTIDE-BINDING / SERINE/THREONINE-PROTEIN KINASE / CELL CYCLE COMPLEX / KINASE / MITOSIS / TRANSFERASE
Function / homology
Function and homology information


cellular response to luteinizing hormone stimulus / cellular response to cocaine / cell cycle G1/S phase transition / mitotic cell cycle phase transition / male pronucleus / female pronucleus / cellular response to insulin-like growth factor stimulus / cellular response to leptin stimulus / response to glucagon / cyclin-dependent protein serine/threonine kinase regulator activity ...cellular response to luteinizing hormone stimulus / cellular response to cocaine / cell cycle G1/S phase transition / mitotic cell cycle phase transition / male pronucleus / female pronucleus / cellular response to insulin-like growth factor stimulus / cellular response to leptin stimulus / response to glucagon / cyclin-dependent protein serine/threonine kinase regulator activity / cochlea development / cellular response to platelet-derived growth factor stimulus / regulation of DNA replication / regulation of cyclin-dependent protein serine/threonine kinase activity / cyclin A1-CDK2 complex / cyclin E1-CDK2 complex / cyclin E2-CDK2 complex / positive regulation of DNA-dependent DNA replication initiation / cyclin A2-CDK2 complex / Y chromosome / cyclin-dependent protein kinase activity / X chromosome / histone phosphorylation / centrosome duplication / centriole replication / cyclin-dependent kinase / cyclin-dependent protein serine/threonine kinase activity / condensed chromosome / cyclin-dependent protein kinase holoenzyme complex / Cajal body / cellular response to nitric oxide / mitotic G1 DNA damage checkpoint / cyclin binding / regulation of gene silencing / potassium ion transport / meiotic cell cycle / cellular response to estradiol stimulus / chromosome, telomeric region / animal organ regeneration / G1/S transition of mitotic cell cycle / positive regulation of fibroblast proliferation / anaphase-promoting complex-dependent catabolic process / regulation of G2/M transition of mitotic cell cycle / DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest / cellular response to hypoxia / Ras protein signal transduction / G2/M transition of mitotic cell cycle / transcription factor complex / regulation of signal transduction by p53 class mediator / DNA replication / endosome / peptidyl-serine phosphorylation / protein deubiquitination / centrosome / cell division / DNA repair / protein domain specific binding / protein serine/threonine kinase activity / protein phosphorylation / viral process / positive regulation of cell population proliferation / protein kinase binding / positive regulation of transcription, DNA-templated / negative regulation of transcription by RNA polymerase II / magnesium ion binding / nucleoplasm / ATP binding / nucleus / cytosol / cytoplasm
Protein kinase-like domain superfamily / Cyclin-A, N-terminal / Protein kinase domain / Cyclin, C-terminal domain / Cyclin, N-terminal / Serine/threonine-protein kinase, active site / Protein kinase, ATP binding site / Cyclin-like / Cyclin-like superfamily / Cyclin ...Protein kinase-like domain superfamily / Cyclin-A, N-terminal / Protein kinase domain / Cyclin, C-terminal domain / Cyclin, N-terminal / Serine/threonine-protein kinase, active site / Protein kinase, ATP binding site / Cyclin-like / Cyclin-like superfamily / Cyclin / Protein kinase domain / Cyclin, N-terminal domain / Cyclin, C-terminal domain / Cyclin-like / Cyclin A; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Cyclin-dependent kinase 2 / Cyclin-A2
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsPratt, D.J. / Bentley, J. / Jewsbury, P. / Boyle, F.T. / Endicott, J.A. / Noble, M.E.M.
CitationJournal: J.Med.Chem. / Year: 2006
Title: Dissecting the Determinants of Cyclin-Dependent Kinase 2 and Cyclin-Dependent Kinase 4 Inhibitor Selectivity.
Authors: Pratt, D.J. / Bentley, J. / Jewsbury, P. / Boyle, F.T. / Endicott, J.A. / Noble, M.E.M.
Validation Report
SummaryFull reportAbout validation report
History
DepositionJun 27, 2006Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 6, 2006Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Advisory / Version format compliance

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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)129,4088
Polymers128,3874
Non-polymers1,0214
Water5,567309
1
A: CELL DIVISION PROTEIN KINASE 2
B: CYCLIN-A2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,7044
Polymers64,1932
Non-polymers5112
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4310 Å2
ΔGint-20.2 kcal/mol
Surface area22950 Å2
MethodPISA
2
C: CELL DIVISION PROTEIN KINASE 2
D: CYCLIN-A2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,7044
Polymers64,1932
Non-polymers5112
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4220 Å2
ΔGint-20.8 kcal/mol
Surface area22080 Å2
MethodPISA
Unit cell
γ
α
β
Length a, b, c (Å)73.894, 135.324, 148.323
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 / Refine code: 4

Dom-IDEns-IDAuth asym-IDAuth seq-ID
11A0 - 298
21C0 - 298
12B175 - 432
22D175 - 432

NCS ensembles:
ID
1
2

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Components

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


Mass: 34308.652 Da / Num. of mol.: 2 / Details: PHOSPHOTHREONINE 160 / Mutation: YES
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Description: WILD TYPE GENE WAS A GIFT FROM DR D.O.MORGAN / Plasmid: PGEX 6P-1 / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P24941, EC: 2.7.1.37
#2: Protein/peptide CYCLIN-A2 / HUMAN CYCLIN A / CYCLIN-A


Mass: 29884.605 Da / Num. of mol.: 2 / Details: MONOTHIOGLYCEROL ADDUCT ON RESIDUE 193 / Fragment: A3, RESIDUES 174-432
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human)
Description: FULL LENGTH CYCLIN A WAS A GIFT FROM DR M.DOREE
Plasmid: PET21D / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P20248
#3: Chemical ChemComp-4SP / O6-CYCLOHEXYLMETHOXY-2-(4'-SULPHAMOYLANILINO) PURINE


Mass: 402.471 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C18H22N6O3S
#4: Chemical ChemComp-SGM / MONOTHIOGLYCEROL


Mass: 108.159 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O2S / 3-Mercaptopropane-1,2-diol
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 309 / Source method: isolated from a natural source / Formula: H2O / Water
Compound detailsENGINEERED RESIDUE IN CHAIN A, PHE 82 TO HIS ENGINEERED RESIDUE IN CHAIN A, LEU 83 TO VAL ...ENGINEERED RESIDUE IN CHAIN A, PHE 82 TO HIS ENGINEERED RESIDUE IN CHAIN A, LEU 83 TO VAL ENGINEERED RESIDUE IN CHAIN A, HIS 84 TO ASP ENGINEERED RESIDUE IN CHAIN C, PHE 82 TO HIS ENGINEERED RESIDUE IN CHAIN C, LEU 83 TO VAL ENGINEERED RESIDUE IN CHAIN C, HIS 84 TO ASP
Sequence detailsGPGS INTRODUCED AT N-TERMINUS BY CLONING. M INTRODUCED AT N-TERMINUS BY CLONING.

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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: 2.93 Å3/Da / Density % sol: 57.75 %
Crystal growpH: 7
Details: DROPLET CONTAINED PROTEIN AT A CONCENTRATION OF 10 MG ML-1 IN 40 MM HEPES PH 7.0 CONTAINING 1 MM DTT, 200 MM NACL, 5% V/V DMSO AND 1MM INHIBITOR. THE RESERVOIR SOLUTION CONTAINED 0.8 M KCL AND 1.2 M (NH4)2SO4 IN 40 MM HEPES PH 7.0 AND 5 MM DTT.

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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 21, 2002
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.933 Å / Relative weight: 1
ReflectionResolution: 2.3→65.9 Å / Num. obs: 64531 / % possible obs: 97.1 % / Observed criterion σ(I): 0 / Redundancy: 2.6 % / Rmerge(I) obs: 0.13 / Net I/σ(I): 3.6
Reflection shellResolution: 2.3→2.41 Å / Redundancy: 2.5 % / Rmerge(I) obs: 0.32 / Mean I/σ(I) obs: 2.3 / % possible all: 94.4

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Processing

Software
NameVersionClassification
REFMAC5.2.0019refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1H1S
Resolution: 2.3→100 Å / Cor.coef. Fo:Fc: 0.928 / Cor.coef. Fo:Fc free: 0.895 / SU B: 14.391 / SU ML: 0.164 / TLS residual ADP flag: LIKELY RESIDUAL / Cross valid method: THROUGHOUT / ESU R: 0.301 / ESU R Free: 0.231 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.255 3271 5.1 %RANDOM
Rwork0.212 ---
Obs0.214 61234 96.5 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 14.38 Å2
Baniso -1Baniso -2Baniso -3
1--1.25 Å20 Å20 Å2
2--0.73 Å20 Å2
3---0.52 Å2
Refinement stepCycle: LAST / Resolution: 2.3→100 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8646 0 68 309 9023
Refine LS restraints

Refinement-ID: X-RAY DIFFRACTION

TypeDev idealDev ideal targetNumber
r_bond_refined_d0.0120.0228929
r_bond_other_d
r_angle_refined_deg1.4091.98712118
r_angle_other_deg
r_dihedral_angle_1_deg5.9151068
r_dihedral_angle_2_deg41.32723.953382
r_dihedral_angle_3_deg16.99151574
r_dihedral_angle_4_deg17.6181544
r_chiral_restr0.0920.21376
r_gen_planes_refined0.0050.026590
r_gen_planes_other
r_nbd_refined0.2040.24185
r_nbd_other
r_nbtor_refined0.3020.26053
r_nbtor_other
r_xyhbond_nbd_refined0.1870.2441
r_xyhbond_nbd_other
r_metal_ion_refined
r_metal_ion_other
r_symmetry_vdw_refined0.2210.248
r_symmetry_vdw_other
r_symmetry_hbond_refined0.1750.28
r_symmetry_hbond_other
r_symmetry_metal_ion_refined
r_symmetry_metal_ion_other
r_mcbond_it0.691.55540
r_mcbond_other
r_mcangle_it1.13428734
r_mcangle_other
r_scbond_it1.73133868
r_scbond_other
r_scangle_it2.6474.53384
r_scangle_other
r_long_range_B_refined
r_long_range_B_other
r_rigid_bond_restr
r_sphericity_free
r_sphericity_bonded
Refine LS restraints NCS

Refinement-ID: X-RAY DIFFRACTION

Ens-IDDom-IDAuth asym-IDNumberTypeRms dev position (Å)Weight position
11A2126medium positional0.420.5
12C2126medium positional0.420.5
21B2045medium positional0.280.5
22D2045medium positional0.280.5
11A2126medium thermal0.952
12C2126medium thermal0.952
21B2045medium thermal0.712
22D2045medium thermal0.712
LS refinement shellResolution: 2.3→2.36 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rfree0.312 234
Rwork0.235 4306
Refinement TLS params.

Method: refined / Refinement-ID: X-RAY DIFFRACTION

IDL112)L122)L132)L222)L232)L332)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T112)T122)T132)T222)T232)T332)Origin x (Å)Origin y (Å)Origin z (Å)
11.00740.3736-0.21210.8287-0.20030.7790.03250.03710.0045-0.1097-0.0040.0793-0.0504-0.074-0.0284-0.170.02-0.0066-0.15520.0043-0.15288.462643.047464.2985
21.1909-0.23940.37981.6097-0.12391.7914-0.0485-0.10010.09990.06930.0566-0.0555-0.2119-0.0066-0.008-0.1389-0.01360.0287-0.1661-0.0303-0.157322.109767.667377.5917
31.45470.2415-0.61331.6343-0.22651.39350.05960.01210.10720.1547-0.1449-0.1769-0.23670.39850.08540.0609-0.1034-0.06450.15630.132-0.032344.422781.619542.6702
42.7590.4250.16562.2336-0.25251.06750.08050.1825-0.44140.0331-0.12-0.56730.23050.53010.03950.05780.1716-0.00750.18980.040.061844.823248.497939.0209
Refinement TLS group

Refinement-ID: X-RAY DIFFRACTION

IDRefine TLS-IDAuth asym-IDAuth seq-ID
11A0 - 298
21A1298
32B175 - 432
43C0 - 298
53C1297
64D175 - 432

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