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

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Basic information

Entry
Database: PDB / ID: 4bcp
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


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 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 / 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 / protein serine/threonine kinase activity / centrosome / DNA-templated transcription / positive regulation of cell population proliferation / protein kinase binding / positive regulation of DNA-templated transcription
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-T3C / Cyclin-A2 / Cyclin-dependent kinase 2
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.26 Å
AuthorsHole, A.J. / Baumli, S. / Wang, S. / Endicott, J.A. / Noble, M.E.M.
CitationJournal: J.Med.Chem. / Year: 2013
Title: Substituted 4-(Thiazol-5-Yl)-2-(Phenylamino)Pyrimidines are Highly Active Cdk9 Inhibitors: Synthesis, X-Ray Crystal Structure, Sar and Anti-Cancer Activities.
Authors: Shao, H. / Shi, S. / Huang, S. / Hole, A. / Abbas, A.Y. / Baumli, S. / Liu, X. / Lam, F. / Foley, D.W. / Fischer, P.M. / Noble, M. / Endicott, J.A. / Pepper, C. / Wang, S.
History
DepositionOct 2, 2012Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 17, 2013Provider: repository / Type: Initial release
Revision 1.1Aug 7, 2013Group: Refinement description

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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)129,86611
Polymers128,5094
Non-polymers1,3587
Water6,539363
1
A: CYCLIN-DEPENDENT KINASE 2
B: CYCLIN-A2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,9876
Polymers64,2542
Non-polymers7334
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3670 Å2
ΔGint-31.8 kcal/mol
Surface area23350 Å2
MethodPISA
2
C: CYCLIN-DEPENDENT KINASE 2
D: CYCLIN-A2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,8795
Polymers64,2542
Non-polymers6253
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3650 Å2
ΔGint-31.9 kcal/mol
Surface area22220 Å2
MethodPISA
Unit cell
Length a, b, c (Å)73.810, 134.553, 149.168
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: 30053.717 Da / Num. of mol.: 2 / 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

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Non-polymers , 4 types, 370 molecules

#3: Chemical ChemComp-T3C / 2-[[3-(1,4-diazepan-1-yl)phenyl]amino]-4-[4-methyl-2-(methylamino)-1,3-thiazol-5-yl]pyrimidine-5-carbonitrile


Mass: 420.534 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H24N8S
#4: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#5: Chemical ChemComp-SGM / MONOTHIOGLYCEROL / 3-Mercaptopropane-1,2-diol


Mass: 108.159 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C3H8O2S
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 363 / 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: 2.26→29.83 Å / Num. obs: 69656 / % possible obs: 99.2 % / Redundancy: 4.42 % / Biso Wilson estimate: 39.1 Å2 / Rmerge(I) obs: 0.07 / Net I/σ(I): 8.91
Reflection shellResolution: 2.26→2.38 Å / Redundancy: 4.41 % / Rmerge(I) obs: 0.5 / Mean I/σ(I) obs: 1.58 / % possible all: 96.6

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Processing

Software
NameVersionClassification
PHENIX(PHENIX.REFINE)refinement
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.26→29.684 Å / SU ML: 0.53 / σ(F): 0 / Phase error: 21.5 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2171 3512 5.1 %
Rwork0.181 --
obs0.1828 69591 99.07 %
Solvent computationShrinkage radii: 0.72 Å / VDW probe radii: 1 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 48.057 Å2 / ksol: 0.37 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1--4.1006 Å20 Å20 Å2
2--3.022 Å20 Å2
3---1.0786 Å2
Refinement stepCycle: LAST / Resolution: 2.26→29.684 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8708 0 88 363 9159
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0039091
X-RAY DIFFRACTIONf_angle_d0.70212336
X-RAY DIFFRACTIONf_dihedral_angle_d15.7123404
X-RAY DIFFRACTIONf_chiral_restr0.051384
X-RAY DIFFRACTIONf_plane_restr0.0031534
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.2603-2.29120.28661320.23092296X-RAY DIFFRACTION88
2.2912-2.32390.24621170.20832658X-RAY DIFFRACTION100
2.3239-2.35860.24911400.21522626X-RAY DIFFRACTION100
2.3586-2.39550.27091290.21392649X-RAY DIFFRACTION100
2.3955-2.43470.27691470.22432604X-RAY DIFFRACTION100
2.4347-2.47670.27251360.22732651X-RAY DIFFRACTION100
2.4767-2.52170.27051320.21872638X-RAY DIFFRACTION100
2.5217-2.57020.29711220.21412648X-RAY DIFFRACTION100
2.5702-2.62260.2591280.2152663X-RAY DIFFRACTION100
2.6226-2.67960.26021380.21112630X-RAY DIFFRACTION100
2.6796-2.74190.24061370.22442657X-RAY DIFFRACTION100
2.7419-2.81040.28411500.22562598X-RAY DIFFRACTION100
2.8104-2.88630.27851510.21652628X-RAY DIFFRACTION100
2.8863-2.97120.27041450.21692665X-RAY DIFFRACTION100
2.9712-3.0670.21481360.19642664X-RAY DIFFRACTION100
3.067-3.17650.26641550.19652624X-RAY DIFFRACTION100
3.1765-3.30350.24161420.18482642X-RAY DIFFRACTION100
3.3035-3.45360.18061650.1692660X-RAY DIFFRACTION100
3.4536-3.63540.20791360.16212678X-RAY DIFFRACTION100
3.6354-3.86270.19441350.1572666X-RAY DIFFRACTION99
3.8627-4.16020.18821520.15712661X-RAY DIFFRACTION99
4.1602-4.57750.17421420.13782670X-RAY DIFFRACTION99
4.5775-5.23680.15731400.14582701X-RAY DIFFRACTION99
5.2368-6.58590.24151580.1882685X-RAY DIFFRACTION98
6.5859-29.6860.1771470.17222817X-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)
11.0257-0.39520.88721.75071.13662.18380.0811-0.3542-0.22810.2203-0.13490.24270.2954-0.52540.04740.2489-0.0390.03030.34680.05630.279810.547913.510823.9945
21.6391-0.30620.70110.8537-0.01450.9359-0.00740.08990.1827-0.0030.01980.0656-0.0535-0.09520.00520.1435-0.00790.0350.26170.06980.24755.403531.28764.2184
31.70580.6273-0.37571.8685-0.43771.8815-0.07320.2778-0.1093-0.13380.128-0.0870.3054-0.0222-0.05410.19280.0008-0.04030.2025-0.05180.167321.9699-0.3881-3.423
41.8270.33361.072.25150.46991.51260.2375-0.3405-0.1530.0276-0.11480.15920.3626-0.2229-0.07950.440.0086-0.03140.34030.08270.284227.962-8.920230.8532
51.6591-0.24550.45452.3506-0.54951.50020.0735-0.0794-0.136-0.1091-0.1139-0.40770.32450.49580.04510.36490.15560.06660.49890.08780.332552.3691-17.087531.9287
61.9462-0.71760.11562.0779-0.13751.5313-0.0263-0.05550.4456-0.1714-0.0496-0.6613-0.11550.37640.06820.3149-0.13410.05810.28880.03670.426545.049318.741535.0566
72.63790.58261.20981.0429-0.47481.3364-0.287-0.11440.00620.1628-0.2941-0.1908-0.014-0.0060.37960.713-0.1748-0.12580.6940.19570.52455.984822.911923.2201
83.5164-4.4528-2.51835.88643.11236.04860.08380.2819-0.10070.23310.03080.0259-0.24860.11360.01930.90110.0282-0.19691.37820.17721.15828.00666.391219.9396
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 AND (RESSEQ 176:432)
7X-RAY DIFFRACTION7CHAIN A AND (RESSEQ 1299)
8X-RAY DIFFRACTION8CHAIN D AND (RESSEQ 1433:1434)

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