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

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Basic information

Entry
Database: PDB / ID: 4bcn
TitleStructure of CDK2 in complex with cyclin A and a 2-amino-4-heteroaryl- pyrimidine inhibitor
Components
  • (CYCLIN-A2) x 2
  • 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


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 / response to glucagon ...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 / response to glucagon / cellular response to cocaine / 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 / 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 / positive regulation of fibroblast proliferation / 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 / 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 / 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-T9N / Cyclin-A2 / Cyclin-dependent kinase 2
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.1 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 1.0Mar 6, 2013Provider: repository / Type: Initial release

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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)129,3858
Polymers128,5164
Non-polymers8694
Water12,376687
1
C: CYCLIN-DEPENDENT KINASE 2
D: CYCLIN-A2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,6714
Polymers64,2362
Non-polymers4342
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3320 Å2
ΔGint-31.1 kcal/mol
Surface area23330 Å2
MethodPISA
2
A: CYCLIN-DEPENDENT KINASE 2
B: CYCLIN-A2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,7144
Polymers64,2792
Non-polymers4342
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3220 Å2
ΔGint-29.4 kcal/mol
Surface area23480 Å2
MethodPISA
Unit cell
Length a, b, c (Å)74.050, 135.080, 148.190
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 , 3 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: 30078.771 Da / Num. of mol.: 1 / Fragment: RESIDUES 171-432
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli) / References: UniProt: P20248
#3: Protein CYCLIN-A2 / CYCLIN-A


Mass: 30035.682 Da / Num. of mol.: 1 / Fragment: RESIDUES 171-431
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli) / References: UniProt: P20248

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Non-polymers , 3 types, 691 molecules

#4: Chemical ChemComp-T9N / 2-[(3-hydroxyphenyl)amino]-4-[4-methyl-2-(methylamino)-1,3-thiazol-5-yl]pyrimidine-5-carbonitrile


Mass: 338.387 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C16H14N6OS
#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.: 687 / 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: I02 / Wavelength: 0.979
DetectorType: ADSC CCD / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2.07→49.91 Å / Num. obs: 87330 / % possible obs: 99.9 % / Redundancy: 4.02 % / Biso Wilson estimate: 31.05 Å2 / Rmerge(I) obs: 0.08 / Net I/σ(I): 6.68
Reflection shellResolution: 2.1→2.21 Å / Redundancy: 4.05 % / Rmerge(I) obs: 0.55 / Mean I/σ(I) obs: 1.38 / % possible all: 99.9

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Processing

Software
NameVersionClassification
PHENIX(PHENIX.REFINE)refinement
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.1→49.915 Å / SU ML: 0.62 / σ(F): 1.34 / Phase error: 20.37 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2191 4376 5 %
Rwork0.1838 --
obs0.1856 87253 99.81 %
Solvent computationShrinkage radii: 0.83 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 47.471 Å2 / ksol: 0.374 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1--1.8624 Å20 Å20 Å2
2--1.5466 Å20 Å2
3---0.3157 Å2
Refinement stepCycle: LAST / Resolution: 2.1→49.915 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8904 0 58 687 9649
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0049221
X-RAY DIFFRACTIONf_angle_d0.77412528
X-RAY DIFFRACTIONf_dihedral_angle_d13.8353455
X-RAY DIFFRACTIONf_chiral_restr0.0551408
X-RAY DIFFRACTIONf_plane_restr0.0031569
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.1-2.12390.28261450.25192733X-RAY DIFFRACTION100
2.1239-2.14890.32351330.24862738X-RAY DIFFRACTION100
2.1489-2.17510.3061480.23372717X-RAY DIFFRACTION100
2.1751-2.20260.27251560.2212757X-RAY DIFFRACTION100
2.2026-2.23160.27481480.21862715X-RAY DIFFRACTION100
2.2316-2.26210.29181440.22462728X-RAY DIFFRACTION100
2.2621-2.29450.2461340.20652732X-RAY DIFFRACTION100
2.2945-2.32870.23031350.1992773X-RAY DIFFRACTION100
2.3287-2.36510.23881470.20472721X-RAY DIFFRACTION100
2.3651-2.40390.23911280.1892754X-RAY DIFFRACTION100
2.4039-2.44530.25161410.1912742X-RAY DIFFRACTION100
2.4453-2.48980.23551570.19222723X-RAY DIFFRACTION100
2.4898-2.53770.20751380.18952753X-RAY DIFFRACTION100
2.5377-2.58950.25711470.18752746X-RAY DIFFRACTION100
2.5895-2.64580.26491250.19592788X-RAY DIFFRACTION100
2.6458-2.70730.21041480.19942738X-RAY DIFFRACTION100
2.7073-2.7750.25821300.20262760X-RAY DIFFRACTION100
2.775-2.850.26321530.20512761X-RAY DIFFRACTION100
2.85-2.93390.25961570.20682720X-RAY DIFFRACTION100
2.9339-3.02860.23031270.20572770X-RAY DIFFRACTION100
3.0286-3.13680.21921520.20092788X-RAY DIFFRACTION100
3.1368-3.26240.25111340.19382750X-RAY DIFFRACTION100
3.2624-3.41080.21431660.18492765X-RAY DIFFRACTION100
3.4108-3.59060.18561420.16752779X-RAY DIFFRACTION100
3.5906-3.81550.19341530.15632789X-RAY DIFFRACTION100
3.8155-4.110.19021520.15022813X-RAY DIFFRACTION100
4.11-4.52330.14811590.13892774X-RAY DIFFRACTION100
4.5233-5.17730.1761630.14852796X-RAY DIFFRACTION100
5.1773-6.52050.23151490.19742828X-RAY DIFFRACTION99
6.5205-49.92890.21071650.17952926X-RAY DIFFRACTION98
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)
11.0651-0.12220.71641.76010.90612.2990.067-0.215-0.13370.1988-0.17780.19110.1892-0.42310.09980.1833-0.0087-0.00030.2130.01570.171910.549714.396324.2879
21.545-0.10670.57490.7168-0.30150.87970.02520.05060.21340.0005-0.01360.0423-0.0648-0.05750.00680.08730.00290.02480.13260.01870.18014.7131.3364.2277
31.4380.2813-0.3931.741-0.25771.8259-0.04710.1579-0.0862-0.12450.073-0.08270.2997-0.0033-0.03340.16460.0079-0.01950.1398-0.02660.149121.5052-0.1863-2.8189
41.37140.27150.71031.94021.18710.97450.2201-0.289-0.22170.3397-0.1766-0.0720.48490.0388-0.02240.3960.0466-0.04040.32360.10690.22528.6705-7.824731.6193
51.3573-0.1770.44162.5579-1.04261.58550.1394-0.0339-0.1801-0.2143-0.4699-0.80460.32820.77440.29360.32280.20130.06430.72430.29080.513955.1687-14.158234.1373
62.2185-0.1894-0.4382.4859-0.45562.00810.0863-0.2690.35580.0368-0.2862-0.5521-0.28390.73310.17110.2907-0.1871-0.06480.4760.09930.319544.607120.485234.3956
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

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