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- PDB-3kb7: Crystal structure of Polo-like kinase 1 in complex with a pyrazol... -

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Basic information

Entry
Database: PDB / ID: 3kb7
TitleCrystal structure of Polo-like kinase 1 in complex with a pyrazoloquinazoline inhibitor
ComponentsSerine/threonine-protein kinase PLK1
KeywordsTRANSFERASE / PROTEIN KINASE / ATP-binding / Cell cycle / Cell division / Kinase / Mitosis / Nucleotide-binding / Nucleus / Phosphoprotein / Polymorphism / Serine/threonine-protein kinase
Function / homology
Function and homology information


Mitotic Telophase/Cytokinesis / regulation of protein localization to cell cortex / Mitotic Metaphase/Anaphase Transition / synaptonemal complex disassembly / Golgi inheritance / regulation of protein binding / Activation of NIMA Kinases NEK9, NEK6, NEK7 / homologous chromosome segregation / polo kinase / mitotic nuclear membrane disassembly ...Mitotic Telophase/Cytokinesis / regulation of protein localization to cell cortex / Mitotic Metaphase/Anaphase Transition / synaptonemal complex disassembly / Golgi inheritance / regulation of protein binding / Activation of NIMA Kinases NEK9, NEK6, NEK7 / homologous chromosome segregation / polo kinase / mitotic nuclear membrane disassembly / nuclear membrane disassembly / protein localization to nuclear envelope / 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 / negative regulation of cyclin-dependent protein serine/threonine kinase activity / outer kinetochore / positive regulation of ubiquitin protein ligase activity / double-strand break repair via alternative nonhomologous end joining / microtubule bundle formation / mitotic chromosome condensation / Polo-like kinase mediated events / regulation of mitotic spindle assembly / Golgi Cisternae Pericentriolar Stack Reorganization / centrosome cycle / regulation of mitotic metaphase/anaphase transition / sister chromatid cohesion / positive regulation of ubiquitin-protein transferase activity / regulation of mitotic cell cycle phase transition / mitotic spindle assembly checkpoint signaling / mitotic spindle pole / mitotic G2 DNA damage checkpoint signaling / regulation of anaphase-promoting complex-dependent catabolic process / establishment of mitotic spindle orientation / mitotic sister chromatid segregation / positive regulation of proteolysis / mitotic cytokinesis / centriolar satellite / spindle midzone / negative regulation of double-strand break repair via homologous recombination / Regulation of MITF-M-dependent genes involved in cell cycle and proliferation / 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 / protein localization to chromatin / Loss of Nlp from mitotic centrosomes / Loss of proteins required for interphase microtubule organization from the centrosome / Recruitment of mitotic centrosome proteins and complexes / positive regulation of peptidyl-threonine phosphorylation / Recruitment of NuMA to mitotic centrosomes / Resolution of Sister Chromatid Cohesion / Anchoring of the basal body to the plasma membrane / centriole / mitotic spindle organization / AURKA Activation by TPX2 / regulation of mitotic cell cycle / Condensation of Prophase Chromosomes / regulation of cytokinesis / RHO GTPases Activate Formins / establishment of protein localization / APC/C:Cdh1 mediated degradation of Cdc20 and other APC/C:Cdh1 targeted proteins in late mitosis/early G1 / protein destabilization / kinetochore / spindle / spindle pole / positive regulation of protein localization to nucleus / Separation of Sister Chromatids / G2/M transition of mitotic cell cycle / microtubule cytoskeleton / The role of GTSE1 in G2/M progression after G2 checkpoint / Regulation of PLK1 Activity at G2/M Transition / double-strand break repair / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / mitotic cell cycle / peptidyl-serine phosphorylation / midbody / microtubule binding / regulation of cell cycle / protein kinase activity / protein ubiquitination / protein phosphorylation / protein serine kinase activity / protein serine/threonine kinase activity / centrosome / negative regulation of apoptotic process / protein kinase binding / chromatin / 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. / Phosphorylase Kinase; domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. ...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. / Phosphorylase Kinase; domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / 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-071 / L(+)-TARTARIC ACID / Serine/threonine-protein kinase PLK1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.5 Å
AuthorsBossi, R.T. / Bertrand, J.A.
CitationJournal: J.Med.Chem. / Year: 2010
Title: Identification of 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivatives as a new class of orally and selective Polo-like kinase 1 inhibitors
Authors: Beria, I. / Ballinari, D. / Bertrand, J.A. / Borghi, D. / Bossi, R.T. / Brasca, M.G. / Cappella, P. / Caruso, M. / Ceccarelli, W. / Ciavolella, A. / Cristiani, C. / Croci, V. / De Ponti, A. ...Authors: Beria, I. / Ballinari, D. / Bertrand, J.A. / Borghi, D. / Bossi, R.T. / Brasca, M.G. / Cappella, P. / Caruso, M. / Ceccarelli, W. / Ciavolella, A. / Cristiani, C. / Croci, V. / De Ponti, A. / Fachin, G. / Ferguson, R.D. / Lansen, J. / Moll, J.K. / Pesenti, E. / Posteri, H. / Perego, R. / Rocchetti, M. / Storici, P. / Volpi, D. / Valsasina, B.
History
DepositionOct 20, 2009Deposition site: RCSB / Processing site: PDBJ
Revision 1.0May 19, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Apr 3, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_conn / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_leaving_atom_flag / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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)36,3244
Polymers35,6601
Non-polymers6643
Water1,35175
1
A: Serine/threonine-protein kinase PLK1
hetero molecules

A: Serine/threonine-protein kinase PLK1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)72,6478
Polymers71,3192
Non-polymers1,3286
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_645y+1,x-1,-z1
Buried area2300 Å2
ΔGint-86 kcal/mol
Surface area28270 Å2
MethodPISA
Unit cell
Length a, b, c (Å)67.352, 67.352, 154.109
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number154
Space group name H-MP3221
Components on special symmetry positions
IDModelComponents
11A-387-

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: 35659.547 Da / Num. of mol.: 1 / Fragment: kinase domain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PLK1 / Cell line (production host): H5 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P53350, polo kinase
#2: Chemical ChemComp-071 / 8-{[2-methoxy-5-(4-methylpiperazin-1-yl)phenyl]amino}-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide


Mass: 448.521 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H28N8O2
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-TLA / L(+)-TARTARIC ACID


Mass: 150.087 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H6O6
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 75 / 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: 2.83 Å3/Da / Density % sol: 56.53 % / Mosaicity: 0.3 °
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 6
Details: 1.2M Na/K tartrate, 25mM Zn acetate, 0.1M MES, pH 6.0, VAPOR DIFFUSION, SITTING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-3 / Wavelength: 1.071568 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: May 4, 2007
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.071568 Å / Relative weight: 1
ReflectionResolution: 2.5→58.328 Å / Num. obs: 14659 / % possible obs: 99.9 % / Redundancy: 5.2 % / Rmerge(I) obs: 0.121 / Rsym value: 0.121 / Net I/σ(I): 12.3
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allRsym value% possible all
2.5-2.645.40.5831.31110020710.583100
2.64-2.85.30.4271.81075720140.427100
2.8-2.995.30.2922.6990718550.292100
2.99-3.235.30.193.9928717550.19100
3.23-3.545.30.1226852516170.122100
3.54-3.955.20.0987.2759914710.09899.9
3.95-4.565.10.0699.5664713090.06999.8
4.56-5.594.70.05312.6530211240.05399.6
5.59-7.915.10.04813.645308890.04899.9
7.91-77.154.60.0428.725395540.04299.9

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation3 Å58.33 Å
Translation3 Å58.33 Å

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Processing

Software
NameVersionClassificationNB
MOSFLMdata reduction
SCALA3.2.25data scaling
MOLREPphasing
REFMACrefinement
PDB_EXTRACT3.005data extraction
DNAdata collection
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: In-house available PLK1 crystal structure

Resolution: 2.5→58.32 Å / Cor.coef. Fo:Fc: 0.929 / Cor.coef. Fo:Fc free: 0.839 / WRfactor Rfree: 0.268 / WRfactor Rwork: 0.193 / Occupancy max: 1 / Occupancy min: 0.5 / FOM work R set: 0.901 / SU B: 5.905 / SU ML: 0.136 / SU R Cruickshank DPI: 0.405 / SU Rfree: 0.317 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.416 / ESU R Free: 0.326 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.30317 736 5 %RANDOM
Rwork0.20769 ---
obs0.21211 14616 99.9 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 65.63 Å2 / Biso mean: 30.807 Å2 / Biso min: 6.85 Å2
Baniso -1Baniso -2Baniso -3
1-1.7 Å20.85 Å20 Å2
2--1.7 Å20 Å2
3----2.55 Å2
Refinement stepCycle: LAST / Resolution: 2.5→58.32 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2353 0 44 75 2472
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.0222451
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.6572.0043307
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.3635287
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.73622.5108
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.44415441
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.4891522
X-RAY DIFFRACTIONr_chiral_restr0.1180.2362
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.021828
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.2340.21137
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined0.320.21647
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1650.2125
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined0.0920.22
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2540.234
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1130.24
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.6781.51491
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.17322351
X-RAY DIFFRACTIONr_scbond_it1.81231079
X-RAY DIFFRACTIONr_scangle_it2.7714.5956
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.5→2.565 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.379 57 -
Rwork0.268 980 -
all-1037 -
obs--100 %

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