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- PDB-4a4l: CRYSTAL STRUCTURE OF POLO-LIKE KINASE 1 IN COMPLEX WITH A 5-(2-AM... -

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Entry
Database: PDB / ID: 4a4l
TitleCRYSTAL STRUCTURE OF POLO-LIKE KINASE 1 IN COMPLEX WITH A 5-(2-AMINO- PYRIMIDIN-4-YL)-1H-PYRROLE INHIBITOR
ComponentsSERINE/THREONINE-PROTEIN KINASE PLK1
KeywordsTRANSFERASE
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 / mitotic nuclear membrane disassembly / Activation of NIMA Kinases NEK9, NEK6, NEK7 / 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 / mitotic nuclear membrane disassembly / Activation of NIMA Kinases NEK9, NEK6, NEK7 / 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 / outer kinetochore / Phosphorylation of the APC/C / anaphase-promoting complex binding / regulation of protein binding / double-strand break repair via alternative nonhomologous end joining / negative regulation of cyclin-dependent protein serine/threonine kinase activity / positive regulation of ubiquitin protein ligase activity / regulation of mitotic spindle assembly / microtubule bundle formation / Polo-like kinase mediated events / mitotic chromosome condensation / Golgi Cisternae Pericentriolar Stack Reorganization / positive regulation of ubiquitin-protein transferase activity / sister chromatid cohesion / regulation of mitotic metaphase/anaphase transition / centrosome cycle / regulation of mitotic cell cycle phase transition / mitotic spindle assembly checkpoint signaling / mitotic spindle pole / regulation of mitotic cell cycle / 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 / 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 / spindle / kinetochore / 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 / double-strand break repair / Regulation of PLK1 Activity at G2/M Transition / 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 / centrosome / protein serine/threonine kinase activity / chromatin / negative regulation of apoptotic process / protein kinase binding / negative regulation of transcription by RNA polymerase II / magnesium ion binding / 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-939 / L(+)-TARTARIC ACID / Serine/threonine-protein kinase PLK1
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.35 Å
AuthorsBertrand, J.A. / Bossi, R.T.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2012
Title: 5-(2-Amino-Pyrimidin-4-Yl)-1H-Pyrrole and 2-(2-Amino-Pyrimidin-4-Yl)-1,5,6,7-Tetrahydro-Pyrrolo[3,2-C]Pyridin-4-One Derivatives as New Classes of Selective and Orally Available Polo-Like Kinase 1 Inhibitors.
Authors: Caruso, M. / Valsasina, B. / Ballinari, D. / Bertrand, J.A. / Brasca, M.G. / Caldarelli, M. / Cappella, P. / Fiorentini, F. / Gianellini, L.M. / Scolaro, A. / Beria, I.
History
DepositionOct 17, 2011Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 11, 2012Provider: repository / Type: Initial release
Revision 1.1Jan 30, 2019Group: Data collection / Experimental preparation / Category: exptl_crystal_grow / Item: _exptl_crystal_grow.method
Revision 1.2Feb 6, 2019Group: Data collection / Experimental preparation / Category: exptl_crystal_grow / Item: _exptl_crystal_grow.temp
Revision 1.3Apr 3, 2019Group: Data collection / Source and taxonomy / Category: entity_src_gen / Item: _entity_src_gen.pdbx_host_org_cell_line

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: SERINE/THREONINE-PROTEIN KINASE PLK1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,3374
Polymers35,6471
Non-polymers6913
Water95553
1
A: SERINE/THREONINE-PROTEIN KINASE PLK1
hetero molecules

A: SERINE/THREONINE-PROTEIN KINASE PLK1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)72,6758
Polymers71,2932
Non-polymers1,3826
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation5_675x-y+1,-y+2,-z+1/31
Buried area2300 Å2
ΔGint-85.6 kcal/mol
Surface area27550 Å2
MethodPISA
Unit cell
Length a, b, c (Å)66.595, 66.595, 154.035
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number154
Space group name H-MP3221

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Components

#1: Protein SERINE/THREONINE-PROTEIN KINASE PLK1 / POLO-LIKE KINASE 1 / PLK-1 / SERINE/THREONINE-PROTEIN KINASE 13 / STPK13 / PLK1_HUMAN


Mass: 35646.531 Da / Num. of mol.: 1 / Fragment: KINASE DOMAIN, RESIDUES 36-345
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Cell line (production host): High Five / Production host: SPODOPTERA FRUGIPERDA (fall armyworm) / 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-TLA / L(+)-TARTARIC ACID / Tartaric acid


Mass: 150.087 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H6O6
#4: Chemical ChemComp-939 / 1-METHYL-5-(2-{[5-(4-METHYLPIPERAZIN-1-YL)-2-(TRIFLUOROMETHOXY)PHENYL]AMINO}PYRIMIDIN-4-YL)-1H-PYRROLE-3-CARBOXAMIDE


Mass: 475.467 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H24F3N7O2
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 53 / 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: 2.8 Å3/Da / Density % sol: 56.1 % / Description: NONE
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 6
Details: 1.2 M NA/K TARTRATE, 25 MM ZN ACETATE, 0.10 M MES PH 6.0, VAPOR DIFFUSION, SITTING DROP, TEMPERATURE 277 K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-3 / Wavelength: 0.931
DetectorType: ADSC CCD / Detector: CCD / Date: May 5, 2007
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.931 Å / Relative weight: 1
ReflectionResolution: 2.35→57.35 Å / Num. obs: 16356 / % possible obs: 95.9 % / Observed criterion σ(I): 0 / Redundancy: 2.3 % / Biso Wilson estimate: 26.9 Å2 / Rmerge(I) obs: 0.08 / Net I/σ(I): 9.4
Reflection shellResolution: 2.35→2.48 Å / Redundancy: 2.1 % / Rmerge(I) obs: 0.44 / Mean I/σ(I) obs: 2 / % possible all: 78.9

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Processing

Software
NameVersionClassification
CNX2005refinement
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: INTERNAL STRUCTURE WITH AMP-PNP

Resolution: 2.35→28.84 Å / Rfactor Rfree error: 0.01 / Data cutoff high absF: 1698701.39 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.274 808 5 %RANDOM
Rwork0.222 ---
obs0.224 16307 95.1 %-
all-16307 --
Solvent computationSolvent model: FLAT MODEL / Bsol: 47.7489 Å2 / ksol: 0.390391 e/Å3
Displacement parametersBiso mean: 42.4 Å2
Baniso -1Baniso -2Baniso -3
1-9.57 Å27.1 Å20 Å2
2--9.57 Å20 Å2
3----19.13 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.4 Å0.3 Å
Luzzati d res low-5 Å
Luzzati sigma a0.41 Å0.39 Å
Refinement stepCycle: LAST / Resolution: 2.35→28.84 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2353 0 45 53 2451
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.012
X-RAY DIFFRACTIONc_bond_d_na
X-RAY DIFFRACTIONc_bond_d_prot
X-RAY DIFFRACTIONc_angle_d
X-RAY DIFFRACTIONc_angle_d_na
X-RAY DIFFRACTIONc_angle_d_prot
X-RAY DIFFRACTIONc_angle_deg1.3
X-RAY DIFFRACTIONc_angle_deg_na
X-RAY DIFFRACTIONc_angle_deg_prot
X-RAY DIFFRACTIONc_dihedral_angle_d22.2
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d0.86
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it1.391.5
X-RAY DIFFRACTIONc_mcangle_it2.312
X-RAY DIFFRACTIONc_scbond_it2.272
X-RAY DIFFRACTIONc_scangle_it3.42.5
Refine LS restraints NCSNCS model details: NONE
LS refinement shellResolution: 2.35→2.5 Å / Rfactor Rfree error: 0.036 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.362 99 4.7 %
Rwork0.325 2008 -
obs--75.5 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PROTEIN_REP.PARAMPROTEIN.TOP
X-RAY DIFFRACTION2WATER_REP.PARAMWATER.TOP
X-RAY DIFFRACTION3ION.PARAM
X-RAY DIFFRACTION4939.PAR939.TOP
X-RAY DIFFRACTION5TAR.PARTAR.TOP

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