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- PDB-5ta8: Crystal structure of PLK1 in complex with a novel 5,6-dihydroimid... -

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Basic information

Entry
Database: PDB / ID: 5ta8
TitleCrystal structure of PLK1 in complex with a novel 5,6-dihydroimidazolo[1,5-f]pteridine inhibitor
ComponentsSerine/threonine-protein kinase PLK1
KeywordsTransferase/Transferase Inhibitor / PLK1 Inhibitor / Kinase / Structure-based drug design / Antitumor activity / Transferase-Transferase Inhibitor complex
Function / homology
Function and homology information


Mitotic Telophase/Cytokinesis / regulation of protein localization to cell cortex / Mitotic Metaphase/Anaphase Transition / Golgi inheritance / synaptonemal complex disassembly / Activation of NIMA Kinases NEK9, NEK6, NEK7 / mitotic nuclear membrane disassembly / homologous chromosome segregation / protein localization to nuclear envelope / polo kinase ...Mitotic Telophase/Cytokinesis / regulation of protein localization to cell cortex / Mitotic Metaphase/Anaphase Transition / Golgi inheritance / synaptonemal complex disassembly / Activation of NIMA Kinases NEK9, NEK6, NEK7 / mitotic nuclear membrane disassembly / homologous chromosome segregation / protein localization to nuclear envelope / polo kinase / nuclear membrane disassembly / Phosphorylation of Emi1 / metaphase/anaphase transition of mitotic cell cycle / synaptonemal complex / female meiosis chromosome segregation / Phosphorylation of the APC/C / anaphase-promoting complex binding / regulation of protein binding / outer kinetochore / negative regulation of cyclin-dependent protein serine/threonine kinase activity / double-strand break repair via alternative nonhomologous end joining / positive regulation of ubiquitin protein ligase activity / regulation of mitotic spindle assembly / microtubule bundle formation / Polo-like kinase mediated events / Golgi Cisternae Pericentriolar Stack Reorganization / mitotic chromosome condensation / regulation of mitotic metaphase/anaphase transition / sister chromatid cohesion / positive regulation of ubiquitin-protein transferase activity / centrosome cycle / regulation of mitotic cell cycle phase transition / mitotic spindle assembly checkpoint signaling / mitotic spindle pole / regulation of anaphase-promoting complex-dependent catabolic process / mitotic sister chromatid segregation / mitotic G2 DNA damage checkpoint signaling / positive regulation of proteolysis / establishment of mitotic spindle orientation / mitotic cytokinesis / centriolar satellite / spindle midzone / Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal / Cyclin A/B1/B2 associated events during G2/M transition / Mitotic Prometaphase / EML4 and NUDC in mitotic spindle formation / Loss of Nlp from mitotic centrosomes / Loss of proteins required for interphase microtubule organization from the centrosome / Recruitment of mitotic centrosome proteins and complexes / protein localization to chromatin / Resolution of Sister Chromatid Cohesion / Recruitment of NuMA to mitotic centrosomes / regulation of mitotic cell cycle / Anchoring of the basal body to the plasma membrane / centriole / AURKA Activation by TPX2 / mitotic spindle organization / Condensation of Prophase Chromosomes / positive regulation of peptidyl-threonine phosphorylation / regulation of cytokinesis / RHO GTPases Activate Formins / protein destabilization / APC/C:Cdh1 mediated degradation of Cdc20 and other APC/C:Cdh1 targeted proteins in late mitosis/early G1 / establishment of protein localization / kinetochore / spindle / spindle pole / positive regulation of protein localization to nucleus / Separation of Sister Chromatids / The role of GTSE1 in G2/M progression after G2 checkpoint / microtubule cytoskeleton / G2/M transition of mitotic cell cycle / Regulation of PLK1 Activity at G2/M Transition / double-strand break repair / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / mitotic cell cycle / midbody / microtubule binding / peptidyl-serine phosphorylation / protein ubiquitination / regulation of cell cycle / protein kinase activity / protein phosphorylation / protein serine kinase activity / protein serine/threonine kinase activity / centrosome / chromatin / negative regulation of apoptotic process / protein kinase binding / magnesium ion binding / negative regulation of transcription by RNA polymerase II / nucleoplasm / ATP binding / identical protein binding / nucleus / cytosol / cytoplasm
Similarity search - Function
Polo-like kinase 1, catalytic domain / Second polo-box domain / First polo-box domain / POLO box domain superfamily / POLO box duplicated region / POLO box domain / POLO box domain profile. / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 ...Polo-like kinase 1, catalytic domain / Second polo-box domain / First polo-box domain / POLO box domain superfamily / POLO box duplicated region / POLO box domain / POLO box domain profile. / 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-79C / Serine/threonine-protein kinase PLK1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.6 Å
AuthorsSkene, R.J. / Hosfield, D.J.
CitationJournal: Bioorg. Med. Chem. Lett. / Year: 2017
Title: Structure-based design and SAR development of 5,6-dihydroimidazolo[1,5-f]pteridine derivatives as novel Polo-like kinase-1 inhibitors.
Authors: Kiryanov, A. / Natala, S. / Jones, B. / McBride, C. / Feher, V. / Lam, B. / Liu, Y. / Honda, K. / Uchiyama, N. / Kawamoto, T. / Hikichi, Y. / Zhang, L. / Hosfield, D. / Skene, R. / Zou, H. / ...Authors: Kiryanov, A. / Natala, S. / Jones, B. / McBride, C. / Feher, V. / Lam, B. / Liu, Y. / Honda, K. / Uchiyama, N. / Kawamoto, T. / Hikichi, Y. / Zhang, L. / Hosfield, D. / Skene, R. / Zou, H. / Stafford, J. / Cao, X. / Ichikawa, T.
History
DepositionSep 9, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 22, 2017Provider: repository / Type: Initial release
Revision 1.1Mar 8, 2017Group: Database references
Revision 1.2Mar 6, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Serine/threonine-protein kinase PLK1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,1923
Polymers40,5831
Non-polymers6092
Water77543
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)67.364, 67.364, 151.918
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number154
Space group name H-MP3221
Components on special symmetry positions
IDModelComponents
11A-539-

HOH

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Components

#1: Protein Serine/threonine-protein kinase PLK1 / Polo-like kinase 1 / PLK-1 / Serine/threonine-protein kinase 13 / STPK13


Mass: 40582.906 Da / Num. of mol.: 1 / Fragment: UNP residues 13-345
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PLK1, PLK / Production host: unidentified baculovirus / References: UniProt: P53350, polo kinase
#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-79C / 4-[(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino]-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide


Mass: 543.609 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H35F2N7O3
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 43 / 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: 2.45 Å3/Da / Density % sol: 49.83 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop
Details: 0.95 mM succinic acid, 1.7% PEG2000 MME, 0.4 mM zinc acetate, 100 mM HEPES, pH 7.0, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.3 / Wavelength: 0.987 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Oct 11, 2007
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.987 Å / Relative weight: 1
ReflectionResolution: 2.6→50 Å / Num. obs: 9764 / % possible obs: 75.9 % / Redundancy: 6.5 % / Rmerge(I) obs: 0.079 / Χ2: 1.045 / Net I/av σ(I): 17.758 / Net I/σ(I): 12.6 / Num. measured all: 63440
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsDiffraction-ID% possible all
2.6-2.663.90.247128.1
2.66-2.734.10.2130.8
2.73-2.840.185133.9
2.8-2.884.20.202142.8
2.88-2.984.50.189148.2
2.98-3.084.50.189166.4
3.08-3.214.80.2188.4
3.21-3.3560.192198.7
3.35-3.537.40.179199.7
3.53-3.757.80.142199.6
3.75-4.047.80.109199.1
4.04-4.457.70.095199.3
4.45-5.097.50.08199.2
5.09-6.417.30.064199
6.41-507.20.04196.9

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Processing

Software
NameVersionClassification
DENZOdata reduction
SCALEPACKdata scaling
REFMAC5.7.0025refinement
PDB_EXTRACT3.2data extraction
PHASERphasing
RefinementResolution: 2.6→46.31 Å / Cor.coef. Fo:Fc: 0.965 / Cor.coef. Fo:Fc free: 0.931 / SU B: 31.645 / SU ML: 0.305 / SU R Cruickshank DPI: 0.2881 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.368 / Details: U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2467 465 4.8 %RANDOM
Rwork0.1815 ---
obs0.1847 9290 76.05 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 184.71 Å2 / Biso mean: 94.267 Å2 / Biso min: 41.95 Å2
Baniso -1Baniso -2Baniso -3
1-6.39 Å23.2 Å20 Å2
2--6.39 Å20 Å2
3----9.59 Å2
Refinement stepCycle: final / Resolution: 2.6→46.31 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2379 0 40 43 2462
Biso mean--82.6 72.52 -
Num. residues----294
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0192477
X-RAY DIFFRACTIONr_angle_refined_deg1.08623347
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.475293
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.19522.385109
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.95215449
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.6871523
X-RAY DIFFRACTIONr_chiral_restr0.0730.2365
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0211846
LS refinement shellResolution: 2.603→2.67 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.328 14 -
Rwork0.289 245 -
all-259 -
obs--28.28 %
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)
12.159-1.0073-2.3733.59811.01075.9581-0.16210.0147-0.0626-0.3216-0.1361-0.12070.99770.77880.29820.45610.15480.07060.32190.04690.10836.93227.45658.657
22.8859-0.1783-0.72553.56590.44098.40010.19980.1730.0006-0.3636-0.32130.4313-0.3952-0.97030.12150.16740.0587-0.03680.3377-0.09510.1211-13.09839.36570.373
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A38 - 90
2X-RAY DIFFRACTION1A91 - 137
3X-RAY DIFFRACTION2A138 - 190
4X-RAY DIFFRACTION2A191 - 240
5X-RAY DIFFRACTION2A241 - 291
6X-RAY DIFFRACTION2A292 - 330

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