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- PDB-3thb: Structure of PLK1 kinase domain in complex with a benzolactam-der... -

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Basic information

Entry
Database: PDB / ID: 3thb
TitleStructure of PLK1 kinase domain in complex with a benzolactam-derived inhibitor
ComponentsSerine/threonine-protein kinase PLK1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / kinase domain / 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 / homologous chromosome segregation / nuclear membrane disassembly / polo kinase / mitotic nuclear membrane disassembly ...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 / homologous chromosome segregation / nuclear membrane disassembly / polo kinase / mitotic nuclear membrane disassembly / protein localization to nuclear envelope / Phosphorylation of Emi1 / metaphase/anaphase transition of mitotic cell cycle / synaptonemal complex / female meiosis chromosome segregation / regulation of protein binding / anaphase-promoting complex binding / Phosphorylation of the APC/C / outer kinetochore / 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 / sister chromatid cohesion / regulation of mitotic metaphase/anaphase transition / centrosome cycle / positive regulation of ubiquitin-protein transferase activity / regulation of mitotic cell cycle phase transition / mitotic spindle assembly checkpoint signaling / double-strand break repair via alternative nonhomologous end joining / mitotic spindle pole / regulation of anaphase-promoting complex-dependent catabolic process / mitotic G2 DNA damage checkpoint signaling / mitotic sister chromatid segregation / establishment of mitotic spindle orientation / positive regulation of proteolysis / centriolar satellite / mitotic cytokinesis / spindle midzone / negative regulation of double-strand break repair via homologous recombination / 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 / Recruitment of NuMA to mitotic centrosomes / Resolution of Sister Chromatid Cohesion / Anchoring of the basal body to the plasma membrane / regulation of mitotic cell cycle / centriole / AURKA Activation by TPX2 / Condensation of Prophase Chromosomes / mitotic spindle organization / regulation of cytokinesis / positive regulation of peptidyl-threonine phosphorylation / 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 pole / positive regulation of protein localization to nucleus / spindle / Separation of Sister Chromatids / G2/M transition of mitotic cell cycle / The role of GTSE1 in G2/M progression after G2 checkpoint / microtubule cytoskeleton / 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 / regulation of cell cycle / protein kinase activity / protein ubiquitination / protein phosphorylation / protein serine kinase activity / protein serine/threonine kinase activity / centrosome / 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 / cytoplasm / cytosol
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-3TA / Serine/threonine-protein kinase PLK1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.5 Å
AuthorsSintchak, M.D.
CitationJournal: J.Med.Chem. / Year: 2012
Title: Discovery of a Potent and Orally Bioavailable Benzolactam-Derived Inhibitor of Polo-Like Kinase 1 (MLN0905).
Authors: Duffey, M.O. / Vos, T.J. / Adams, R. / Alley, J. / Anthony, J. / Barrett, C. / Bharathan, I. / Bowman, D. / Bump, N.J. / Chau, R. / Cullis, C. / Driscoll, D.L. / Elder, A. / Forsyth, N. / ...Authors: Duffey, M.O. / Vos, T.J. / Adams, R. / Alley, J. / Anthony, J. / Barrett, C. / Bharathan, I. / Bowman, D. / Bump, N.J. / Chau, R. / Cullis, C. / Driscoll, D.L. / Elder, A. / Forsyth, N. / Frazer, J. / Guo, J. / Guo, L. / Hyer, M.L. / Janowick, D. / Kulkarni, B. / Lai, S.J. / Lasky, K. / Li, G. / Li, J. / Liao, D. / Little, J. / Peng, B. / Qian, M.G. / Reynolds, D.J. / Rezaei, M. / Scott, M.P. / Sells, T.B. / Shinde, V. / Shi, Q.J. / Sintchak, M.D. / Soucy, F. / Sprott, K.T. / Stroud, S.G. / Nestor, M. / Visiers, I. / Weatherhead, G. / Ye, Y. / D'Amore, N.
History
DepositionAug 18, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 23, 2011Provider: repository / Type: Initial release
Revision 1.1Jan 25, 2012Group: Database references
Revision 1.2Nov 8, 2017Group: Refinement description / Category: software
Item: _software.classification / _software.contact_author ..._software.classification / _software.contact_author / _software.contact_author_email / _software.date / _software.language / _software.location / _software.name / _software.type / _software.version
Revision 1.3Sep 13, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / entity / pdbx_entity_nonpoly / pdbx_initial_refinement_model / struct_ref_seq_dif / struct_site
Item: _chem_comp.name / _database_2.pdbx_DOI ..._chem_comp.name / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity.pdbx_description / _pdbx_entity_nonpoly.name / _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

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)37,9993
Polymers37,4811
Non-polymers5182
Water00
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
A: Serine/threonine-protein kinase PLK1
hetero molecules

A: Serine/threonine-protein kinase PLK1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)75,9986
Polymers74,9612
Non-polymers1,0374
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation5_555x-y,-y,-z+1/31
Buried area1230 Å2
ΔGint-91 kcal/mol
Surface area27310 Å2
MethodPISA
Unit cell
Length a, b, c (Å)67.668, 67.668, 154.684
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


Mass: 37480.621 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: Escherichia coli (E. coli) / 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-3TA / 9-chloro-2-({5-[3-(dimethylamino)propyl]-2-methylpyridin-3-yl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepine-6-thi one / MLN0905


Mass: 453.003 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H25ClN6S

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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: 2.73 Å3/Da / Density % sol: 54.91 %

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Data collection

Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 31-ID / Wavelength: 0.97989 Å
DetectorType: RAYONIX MX-225 / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97989 Å / Relative weight: 1
ReflectionResolution: 2.5→50 Å / Num. obs: 13436 / % possible obs: 90.6 % / Redundancy: 6.5 % / Rmerge(I) obs: 0.084 / Net I/σ(I): 10.6
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsDiffraction-ID% possible all
2.5-2.594.90.396150.3
2.59-2.6950.376164.3
2.69-2.825.20.343190.2
2.82-2.966.70.399199.8
2.96-3.157.20.2571100
3.15-3.397.20.1821100
3.39-3.737.10.111199.9
3.73-4.2770.0711100
4.27-5.3870.059199.9
5.38-506.50.047198.8

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
REFMAC5.5.0110refinement
PDB_EXTRACT3.1data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2OWB

2owb


Resolution: 2.5→50 Å / Cor.coef. Fo:Fc: 0.936 / Cor.coef. Fo:Fc free: 0.92 / Occupancy max: 1 / Occupancy min: 1 / SU B: 34 / SU ML: 0.321 / Cross valid method: THROUGHOUT / ESU R: 0.599 / ESU R Free: 0.335 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.28591 1317 9.9 %RANDOM
Rwork0.24999 ---
obs0.25347 11950 89.64 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 85.709 Å2
Baniso -1Baniso -2Baniso -3
1-5.57 Å22.79 Å20 Å2
2--5.57 Å20 Å2
3----8.36 Å2
Refinement stepCycle: LAST / Resolution: 2.5→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2242 0 32 0 2274
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0222329
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.3941.9883160
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.1245286
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.00622.95998
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.07515384
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.6221516
X-RAY DIFFRACTIONr_chiral_restr0.0960.2353
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0211762
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.4631.51433
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it2.7322307
X-RAY DIFFRACTIONr_scbond_it4.0513896
X-RAY DIFFRACTIONr_scangle_it6.2824.5853
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.501→2.566 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.407 54 -
Rwork0.378 442 -
obs--47.37 %
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)
11.7517-1.42630.12859.82332.5745.7236-0.6348-0.1061-0.1357-0.45390.0837-0.5003-0.1569-2.9690.55110.19530.2963-0.07871.6203-0.34170.075-52.269118.956414.9651
20.7754-0.027-0.45080.75651.55856.8976-0.0551-0.138-0.0793-0.2294-0.12910.0035-0.5058-0.80470.18410.62350.1342-0.04380.5951-0.02290.3542-40.118715.229214.1512
30.3525-0.0176-0.53290.54780.23813.8411-0.0479-0.1216-0.1642-0.0240.020.0735-0.44350.38940.02790.6507-0.078700.53390.0070.4654-27.298511.641611.0584
41.28960.4908-0.08041.6054-0.29525.6217-0.13370.0139-0.1254-0.4729-0.0377-0.31940.23790.65730.17140.5024-0.02280.08120.49350.01440.4149-23.90524.73290.4834
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A42 - 82
2X-RAY DIFFRACTION2A83 - 154
3X-RAY DIFFRACTION3A155 - 251
4X-RAY DIFFRACTION4A252 - 328

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