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- PDB-2i40: Cdk2/Cyclin A complexed with a thiophene carboxamide inhibitor -

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Basic information

Entry
Database: PDB / ID: 2i40
TitleCdk2/Cyclin A complexed with a thiophene carboxamide inhibitor
Components
  • Cell division protein kinase 2
  • Cyclin-A2
Keywordstransferase/cell cycle / cdk2 / cyclin / kinase / transferase-cell cycle COMPLEX
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 / 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 / cyclin-dependent kinase / 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 G2/M transition of mitotic cell cycle / cyclin binding / post-translational protein modification / meiotic cell cycle / male germ cell nucleus / response to organic substance / 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 / DNA repair / protein serine kinase activity / centrosome / protein serine/threonine kinase activity / DNA-templated transcription / positive regulation of cell population proliferation / protein kinase binding / positive regulation of DNA-templated transcription / negative regulation of transcription by RNA polymerase II / magnesium ion 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 / 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-BLZ / Cyclin-A2 / Cyclin-dependent kinase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.8 Å
AuthorsShewchuk, L.M.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2006
Title: 5-(1H-Benzimidazol-1-yl)-3-alkoxy-2-thiophenecarbonitriles as potent, selective, inhibitors of IKK-epsilon kinase
Authors: Bamborough, P. / Christopher, J.A. / Cutler, G.J. / Dickson, M.C. / Mellor, G.W. / Morey, J.V. / Patel, C.B. / Shewchuk, L.M.
History
DepositionAug 21, 2006Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 10, 2006Provider: repository / Type: Initial release
Revision 1.1May 1, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Advisory / Version format compliance
Revision 1.3Aug 30, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ncs_dom_lim / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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)128,6046
Polymers127,6884
Non-polymers9162
Water4,360242
1
A: Cell division protein kinase 2
B: Cyclin-A2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,3023
Polymers63,8442
Non-polymers4581
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3900 Å2
ΔGint-19 kcal/mol
Surface area23930 Å2
MethodPISA
2
C: Cell division protein kinase 2
D: Cyclin-A2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,3023
Polymers63,8442
Non-polymers4581
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3690 Å2
ΔGint-20 kcal/mol
Surface area23620 Å2
MethodPISA
Unit cell
Length a, b, c (Å)184.882, 184.882, 213.000
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number180
Space group name H-MP6222
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11B
21D
12A
22C
13A
23C
14A
24C
15C
25A

NCS domain segments:

Component-ID: 1

Dom-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDRefine codeAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11GLUGLUASNASN2BB180 - 4258 - 253
21GLUGLUASNASN2DD180 - 4258 - 253
12GLNGLNALAALA4AA85 - 14085 - 140
22GLNGLNALAALA4CC85 - 14085 - 140
13ILEILELEULEU4AA10 - 8310 - 83
23ILEILELEULEU4CC10 - 8310 - 83
14ALAALAALAALA4AA170 - 280170 - 280
24ALAALAALAALA4CC170 - 280170 - 280
15BLZBLZBLZBLZ4CF401
25BLZBLZBLZBLZ4AE301

NCS ensembles :
ID
1
2
3
4
5
Details2 cdk2/cyclinA heterodimers per asu

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Components

#1: Protein Cell division protein 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) / Gene: CDK2 / Plasmid: pFastbac / Production host: Spodoptera frugiperda (fall armyworm) / Strain (production host): Sf9 / References: UniProt: P24941, cyclin-dependent kinase
#2: Protein Cyclin-A2 / Cyclin-A


Mass: 29867.512 Da / Num. of mol.: 2 / Fragment: residues 173-432
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CCNA2, CCN1, CCNA / Species (production host): Escherichia coli / Production host: Escherichia coli BL21 (bacteria) / Strain (production host): BL21 / References: UniProt: P20248
#3: Chemical ChemComp-BLZ / 5-[5,6-BIS(METHYLOXY)-1H-BENZIMIDAZOL-1-YL]-3-{[1-(2-CHLOROPHENYL)ETHYL]OXY}-2-THIOPHENECARBOXAMIDE


Mass: 457.930 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H20ClN3O4S
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 242 / 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: 4.11 Å3/Da / Density % sol: 70.09 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6.7
Details: 1.5 M sodium acetate, 100 mM sodium cacodylate, pH 6.7, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 4 / Detector: CCD / Date: Jul 14, 2003
RadiationMonochromator: monochromator / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.8→160 Å / Num. all: 59552 / Num. obs: 48311 / % possible obs: 95.44 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 2 / Redundancy: 8.4 % / Biso Wilson estimate: 73.5 Å2 / Rmerge(I) obs: 0.11 / Net I/σ(I): 40
Reflection shellResolution: 2.8→2.87 Å / Redundancy: 8 % / Rmerge(I) obs: 0.47 / Mean I/σ(I) obs: 3.78 / Num. unique all: 2695 / % possible all: 73

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Processing

Software
NameVersionClassification
REFMAC5.2.0005refinement
ADSCQUANTUMdata collection
HKL-2000data reduction
HKL-2000data scaling
CNSphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: pdb entry 1FIN

1fin


Resolution: 2.8→160.13 Å / Cor.coef. Fo:Fc: 0.951 / Cor.coef. Fo:Fc free: 0.935 / SU B: 20.005 / SU ML: 0.2 / TLS residual ADP flag: LIKELY RESIDUAL / Isotropic thermal model: isotropic / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 2 / ESU R: 0.49 / ESU R Free: 0.279 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.22176 2579 5.1 %RANDOM
Rwork0.19323 ---
all0.1947 48311 --
obs0.1947 48311 95.44 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 63.453 Å2
Baniso -1Baniso -2Baniso -3
1-1.94 Å20.97 Å20 Å2
2--1.94 Å20 Å2
3----2.91 Å2
Refinement stepCycle: LAST / Resolution: 2.8→160.13 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8772 0 62 242 9076
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0229096
X-RAY DIFFRACTIONr_angle_refined_deg1.121.98512370
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.08651105
X-RAY DIFFRACTIONr_dihedral_angle_2_deg39.28923.984379
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.279151580
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.751541
X-RAY DIFFRACTIONr_chiral_restr0.0770.21404
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.026865
X-RAY DIFFRACTIONr_nbd_refined0.1880.24250
X-RAY DIFFRACTIONr_nbtor_refined0.3040.26279
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1390.2383
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2170.246
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1440.28
X-RAY DIFFRACTIONr_mcbond_it0.3361.55665
X-RAY DIFFRACTIONr_mcangle_it0.59128972
X-RAY DIFFRACTIONr_scbond_it0.82833934
X-RAY DIFFRACTIONr_scangle_it1.3894.53393
Refine LS restraints NCS

Refine-ID: X-RAY DIFFRACTION

Ens-IDDom-IDAuth asym-IDNumberTypeRms dev position (Å)Weight position
11B980tight positional0.030.05
11B987medium positional0.40.5
21A427medium positional0.180.5
31A526medium positional0.430.5
41A874medium positional0.230.5
52C31medium positional0.060.5
11B980tight thermal0.040.5
11B987medium thermal0.32
21A427medium thermal0.332
31A526medium thermal0.262
41A874medium thermal0.232
52C31medium thermal0.542
LS refinement shellResolution: 2.8→2.873 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.303 130 -
Rwork0.274 2695 -
obs-2695 73.07 %
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)
16.328-0.9261-2.02752.79851.20741.9173-0.1505-0.8551-0.56750.4428-0.0894-0.01390.49530.3590.2399-0.0997-0.06260.10330.0867-0.1373-0.1682-16.4282199.3437108.1834
21.69541.0516-2.16372.6732-2.18056.697-0.388-0.1806-0.6905-0.097-0.2158-0.45660.8040.5560.60380.1477-0.10940.2256-0.026-0.15580.1116-28.5581178.565190.2927
33.1170.8038-0.24361.8140.93963.5930.0003-0.19760.20460.1611-0.18310.1287-0.1179-0.18380.1828-0.2387-0.03110.02-0.1232-0.1054-0.2805-21.5091221.9416122.5995
42.4378-0.1083-0.19233.49891.11474.40230.1705-0.0318-0.0599-0.1937-0.29220.640.5574-0.2740.1218-0.0186-0.03860.008-0.1505-0.27560.0875-41.3273176.047765.7117
53.4815-1.0429-0.65773.05530.13712.3334-0.2368-0.029-0.1770.3189-0.0370.21450.1524-0.21340.2738-0.2009-0.09960.14520.0279-0.184-0.2363-48.6624199.6286112.54
62.1668-0.4003-0.00162.2768-0.85883.7755-0.00190.11080.1188-0.0505-0.20750.3576-0.036-0.05610.2094-0.2295-0.02410.0796-0.2595-0.1574-0.1377-19.9284204.511172.7158
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
1X-RAY DIFFRACTION1AA1 - 841 - 84
2X-RAY DIFFRACTION2CC1 - 841 - 84
3X-RAY DIFFRACTION3AA85 - 29785 - 297
4X-RAY DIFFRACTION4CC85 - 29685 - 296
5X-RAY DIFFRACTION5BB175 - 4313 - 259
6X-RAY DIFFRACTION6DD178 - 4326 - 260

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