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- PDB-4bco: Structure of CDK2 in complex with cyclin A and a 2-amino-4-hetero... -

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Basic information

Entry
Database: PDB / ID: 4bco
TitleStructure of CDK2 in complex with cyclin A and a 2-amino-4-heteroaryl- pyrimidine inhibitor
Components
  • CYCLIN-A2
  • CYCLIN-DEPENDENT KINASE 2
KeywordsTRANSFERASE/CELL CYCLE / TRANSFERASE-CELL CYCLE COMPLEX / CDK-CYCLIN COMPLEX / CYCLIN-INHIBITOR / STRUCTURE-BASED DRUG DESIGN
Function / homology
Function and homology information


cell cycle G1/S phase transition / mitotic cell cycle phase transition / cyclin-dependent protein serine/threonine kinase regulator activity / 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 / cyclin-dependent protein kinase activity ...cell cycle G1/S phase transition / mitotic cell cycle phase transition / cyclin-dependent protein serine/threonine kinase regulator activity / 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 / 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 / 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 mitotic cell cycle / regulation of G2/M transition of mitotic cell cycle / cyclin binding / post-translational protein modification / meiotic cell cycle / positive regulation of DNA replication / male germ cell nucleus / response to organic substance / 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 / cellular senescence / Regulation of TP53 Degradation / nuclear envelope / Factors involved in megakaryocyte development and platelet production / Processing of DNA double-strand break ends / 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 / endosome / chromatin remodeling / cell division / protein domain specific binding / protein phosphorylation / DNA repair / protein serine kinase activity / protein serine/threonine kinase activity / centrosome / DNA-templated transcription / positive regulation of cell population proliferation / positive regulation of DNA-templated transcription / negative regulation of transcription by RNA polymerase II / magnesium ion binding / signal transduction / nucleoplasm / ATP binding / nucleus / cytosol / cytoplasm
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
MONOTHIOGLYCEROL / Chem-T6Q / Cyclin-dependent kinase 2 / Cyclin-A2
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
BOS TAURUS (cattle)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.05 Å
AuthorsHole, A.J. / Baumli, S. / Wang, S. / Endicott, J.A. / Noble, M.E.M.
CitationJournal: J.Med.Chem. / Year: 2013
Title: Comparative Structural and Functional Studies of 4-(Thiazol- 5-Yl)-2-(Phenylamino)Pyrimidine-5-Carbonitrile Cdk9 Inhibitors Suggest the Basis for Isotype Selectivity.
Authors: Hole, A.J. / Baumli, S. / Shao, H. / Shi, S. / Pepper, C. / Fischer, P.M. / Wang, S. / Endicott, J.A. / Noble, M.E.M.
History
DepositionOct 2, 2012Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 9, 2013Provider: repository / Type: Initial release
Revision 1.1Feb 27, 2013Group: Database references

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: CYCLIN-DEPENDENT KINASE 2
B: CYCLIN-A2
C: CYCLIN-DEPENDENT KINASE 2
D: CYCLIN-A2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)130,08712
Polymers128,5374
Non-polymers1,5508
Water9,350519
1
A: CYCLIN-DEPENDENT KINASE 2
B: CYCLIN-A2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)65,0436
Polymers64,2682
Non-polymers7754
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3720 Å2
ΔGint-31.9 kcal/mol
Surface area23090 Å2
MethodPISA
2
C: CYCLIN-DEPENDENT KINASE 2
D: CYCLIN-A2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)65,0436
Polymers64,2682
Non-polymers7754
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3860 Å2
ΔGint-32.5 kcal/mol
Surface area21910 Å2
MethodPISA
Unit cell
Length a, b, c (Å)73.902, 133.813, 148.382
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 2 types, 4 molecules ACBD

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


Mass: 34200.602 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: P24941, cyclin-dependent kinase
#2: Protein CYCLIN-A2 / CYCLIN-A


Mass: 30067.744 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) BOS TAURUS (cattle) / Production host: ESCHERICHIA COLI (E. coli) / References: UniProt: P30274

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Non-polymers , 4 types, 527 molecules

#3: Chemical ChemComp-T6Q / 2-[[3-(4-ethanoyl-1,4-diazepan-1-yl)phenyl]amino]-4-[4-methyl-2-(methylamino)-1,3-thiazol-5-yl]pyrimidine-5-carbonitrile


Mass: 462.571 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H26N8OS
#4: Chemical
ChemComp-SGM / MONOTHIOGLYCEROL / 3-Mercaptopropane-1,2-diol


Mass: 108.159 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C3H8O2S
#5: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 519 / 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: 2.9 Å3/Da / Density % sol: 58 % / Description: NONE
Crystal growpH: 7
Details: COCRYSTALS WERE GROWN IN 1-1.25M AMMONIUM SULFATE, 0.5-0.9M KCL, 100MM HEPES, PH 7.0, 5MM DTT AND IN THE PRESENCE OF COMPOUND.

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.9763
DetectorType: ADSC CCD / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9763 Å / Relative weight: 1
ReflectionResolution: 1.58→52.36 Å / Num. obs: 92057 / % possible obs: 99.2 % / Redundancy: 3.22 % / Biso Wilson estimate: 32.61 Å2 / Rmerge(I) obs: 0.08 / Net I/σ(I): 7.16
Reflection shellResolution: 2.05→2.16 Å / Redundancy: 3.29 % / Rmerge(I) obs: 0.54 / Mean I/σ(I) obs: 1.41 / % possible all: 99.4

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Processing

Software
NameVersionClassification
PHENIX(PHENIX.REFINE)refinement
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.05→49.599 Å / SU ML: 0.64 / σ(F): 0 / Phase error: 21.08 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.226 4595 5 %
Rwork0.1887 --
obs0.1906 91969 98.96 %
Solvent computationShrinkage radii: 0.95 Å / VDW probe radii: 1.2 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 44.553 Å2 / ksol: 0.389 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1--0.7662 Å20 Å20 Å2
2---0.0647 Å20 Å2
3---0.8309 Å2
Refinement stepCycle: LAST / Resolution: 2.05→49.599 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8722 0 100 519 9341
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0059050
X-RAY DIFFRACTIONf_angle_d0.90212282
X-RAY DIFFRACTIONf_dihedral_angle_d14.1683386
X-RAY DIFFRACTIONf_chiral_restr0.0611388
X-RAY DIFFRACTIONf_plane_restr0.0041534
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.05-2.07330.28481750.24922809X-RAY DIFFRACTION98
2.0733-2.09770.29871490.24312901X-RAY DIFFRACTION100
2.0977-2.12330.2931520.24282930X-RAY DIFFRACTION100
2.1233-2.15020.26291450.23292903X-RAY DIFFRACTION100
2.1502-2.17850.30851450.2212900X-RAY DIFFRACTION100
2.1785-2.20830.23451350.21512888X-RAY DIFFRACTION100
2.2083-2.23980.29721440.22272965X-RAY DIFFRACTION100
2.2398-2.27330.27411690.21732831X-RAY DIFFRACTION99
2.2733-2.30880.23421290.20912945X-RAY DIFFRACTION100
2.3088-2.34670.27141740.20762876X-RAY DIFFRACTION99
2.3467-2.38710.26751360.21712880X-RAY DIFFRACTION98
2.3871-2.43050.26531480.2212868X-RAY DIFFRACTION99
2.4305-2.47730.30421620.21932911X-RAY DIFFRACTION100
2.4773-2.52780.2631430.20792911X-RAY DIFFRACTION100
2.5278-2.58280.21561840.1962865X-RAY DIFFRACTION100
2.5828-2.64290.21081440.18882959X-RAY DIFFRACTION99
2.6429-2.7090.23691540.19352872X-RAY DIFFRACTION99
2.709-2.78220.2371590.20312929X-RAY DIFFRACTION99
2.7822-2.86410.25391300.20572890X-RAY DIFFRACTION99
2.8641-2.95650.23391590.2082888X-RAY DIFFRACTION97
2.9565-3.06210.23491460.18932902X-RAY DIFFRACTION99
3.0621-3.18470.22741600.1882926X-RAY DIFFRACTION100
3.1847-3.32960.19581390.18212941X-RAY DIFFRACTION99
3.3296-3.50510.20541750.17492899X-RAY DIFFRACTION99
3.5051-3.72470.20971450.17082877X-RAY DIFFRACTION97
3.7247-4.01220.18391700.16752888X-RAY DIFFRACTION98
4.0122-4.41570.19481570.15682964X-RAY DIFFRACTION99
4.4157-5.05410.19051610.15252974X-RAY DIFFRACTION99
5.0541-6.36550.26491440.19323000X-RAY DIFFRACTION98
6.3655-49.61380.19851620.18563082X-RAY DIFFRACTION97
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)
11.58740.16571.00852.0853-1.01552.76310.11540.2671-0.2469-0.3076-0.1502-0.32290.34430.50670.02810.22670.03070.0230.2697-0.03550.2648-10.575813.3096-23.8003
21.78420.19040.96820.7660.00181.0665-0.0015-0.10870.1820.0164-0.0031-0.067-0.04850.06970.01640.13960.00260.02590.2112-0.04570.2154-5.453431.0799-4.178
31.518-0.6213-0.62541.70440.37561.7085-0.0695-0.2279-0.10540.13470.09840.03830.24950.0315-0.03750.177-0.0102-0.03860.19430.03670.159-22.0153-0.39323.5941
41.2945-0.12150.89562.048-1.50211.64540.2710.2399-0.0705-0.1289-0.1476-0.05670.27840.2594-0.12040.37890.0075-0.01680.2819-0.05730.2747-28.3432-9.37-30.6746
51.3538-0.04010.30492.4140.10041.63780.08610.0267-0.16240.1422-0.07140.36770.2885-0.3942-0.00210.2974-0.09920.04780.3398-0.05820.2717-52.367-16.9444-31.7441
61.93220.7387-0.14291.9124-0.09591.46140.01330.01290.39560.20640.0080.5594-0.1538-0.2832-0.00430.28210.09230.05150.2182-0.01070.353-45.028418.7255-34.8806
72.00361.14723.27069.2018-0.56782.0897-0.26190.4381-0.1002-1.0921-0.0963-0.1211-0.11970.23530.36370.35640.0410.0180.2615-0.06020.2867-6.161523.192-24.5163
85.60572.11480.33285.18141.30867.7081-0.13830.1352-0.3754-0.2981-0.0282-0.3578-0.19760.29960.17240.5134-0.1591-0.02520.8134-0.01690.3175-32.4647-19.4808-30.2711
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1CHAIN A AND (RESSEQ 1:85)
2X-RAY DIFFRACTION2CHAIN A AND (RESSEQ 86:298)
3X-RAY DIFFRACTION3CHAIN B
4X-RAY DIFFRACTION4CHAIN C AND (RESSEQ 1:85)
5X-RAY DIFFRACTION5CHAIN C AND (RESSEQ 86:298)
6X-RAY DIFFRACTION6CHAIN D
7X-RAY DIFFRACTION7CHAIN A (RESSEQ 1299)
8X-RAY DIFFRACTION8CHAIN C (RESSEQ 1298)

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