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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


: / cyclin A2-CDK1 complex / cell cycle G1/S phase transition / cellular response to luteinizing hormone stimulus / 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 A2-CDK1 complex / cell cycle G1/S phase transition / cellular response to luteinizing hormone stimulus / 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 / positive regulation of DNA biosynthetic process / cyclin-dependent protein serine/threonine kinase regulator activity / cellular response to insulin-like growth factor stimulus / cyclin A1-CDK2 complex / cyclin E2-CDK2 complex / cyclin E1-CDK2 complex / cyclin A2-CDK2 complex / positive regulation of DNA-templated DNA replication initiation / G2 Phase / Y chromosome / cyclin-dependent protein kinase activity / 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) / centriole replication / Regulation of APC/C activators between G1/S and early anaphase / microtubule organizing center / regulation of DNA replication / telomere maintenance in response to DNA damage / centrosome duplication / G0 and Early G1 / cochlea development / Telomere Extension By Telomerase / animal organ regeneration / Activation of the pre-replicative complex / 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 / positive regulation of DNA replication / meiotic cell cycle / male germ cell nucleus / Cdc20:Phospho-APC/C mediated degradation of Cyclin A / cellular response to estradiol stimulus / G1/S transition of mitotic cell cycle / peptidyl-serine phosphorylation / DNA Damage/Telomere Stress Induced Senescence / potassium ion transport / CDK-mediated phosphorylation and removal of Cdc6 / Meiotic recombination / SCF(Skp2)-mediated degradation of p27/p21 / G2/M transition of mitotic cell cycle / Transcriptional regulation of granulopoiesis / Orc1 removal from chromatin / positive regulation of fibroblast proliferation / Cyclin D associated events in G1 / cellular senescence / Regulation of TP53 Degradation / nuclear envelope / Factors involved in megakaryocyte development and platelet production / Processing of DNA double-strand break ends / regulation of gene expression / Senescence-Associated Secretory Phenotype (SASP) / transcription regulator complex / cellular response to hypoxia / Regulation of TP53 Activity through Phosphorylation / Ras protein signal transduction / chromosome, telomeric region / DNA replication / protein phosphorylation / endosome / Ub-specific processing proteases / chromatin remodeling / protein domain specific binding / cell division / protein serine kinase activity / DNA repair / protein serine/threonine kinase activity / positive regulation of cell population proliferation / DNA-templated transcription / 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-like / Cyclin, C-terminal domain / Cyclin_C ...Cyclin-A, N-terminal APC/C binding region / Cyclin-A N-terminal APC/C binding region / : / Cyclin, C-terminal domain / : / Cyclins signature. / Cyclin / Cyclin-like / Cyclin, C-terminal domain / Cyclin_C / 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-4SP / MONOTHIOGLYCEROL / Cyclin-A2 / Cyclin-dependent kinase 2
Similarity search - Component
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.
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
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
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
Revision 1.3Oct 23, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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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
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:
Dom-IDComponent-IDEns-IDRefine codeAuth asym-IDAuth seq-ID
1114A0 - 298
2114C0 - 298
1124B175 - 432
2124D175 - 432

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: 34308.652 Da / Num. of mol.: 2 / Mutation: YES
Source method: isolated from a genetically manipulated source
Details: PHOSPHOTHREONINE 160 / 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 CYCLIN-A2 / HUMAN CYCLIN A / CYCLIN-A


Mass: 29884.605 Da / Num. of mol.: 2 / Fragment: A3, RESIDUES 174-432
Source method: isolated from a genetically manipulated source
Details: MONOTHIOGLYCEROL ADDUCT ON RESIDUE 193 / 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
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 309 / Source method: isolated from a natural source / Formula: H2O
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
Has protein modificationY
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 ...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

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
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0228929
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.4091.98712118
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.9151068
X-RAY DIFFRACTIONr_dihedral_angle_2_deg41.32723.953382
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.99151574
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.6181544
X-RAY DIFFRACTIONr_chiral_restr0.0920.21376
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.026590
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.2040.24185
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined0.3020.26053
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1870.2441
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2210.248
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1750.28
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.691.55540
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.13428734
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.73133868
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it2.6474.53384
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

Refine-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 / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)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
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A0 - 298
2X-RAY DIFFRACTION1A1298
3X-RAY DIFFRACTION2B175 - 432
4X-RAY DIFFRACTION3C0 - 298
5X-RAY DIFFRACTION3C1297
6X-RAY DIFFRACTION4D175 - 432

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