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- PDB-4j52: Crystal structure of PLK1 in complex with a pyrimidodiazepinone i... -

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Basic information

Entry
Database: PDB / ID: 4j52
TitleCrystal structure of PLK1 in complex with a pyrimidodiazepinone inhibitor
ComponentsSerine/threonine-protein kinase PLK1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / protein serine/threonine kinase / mitosis / oncogenesis / regulation of cell cycle / kinase domain / ATP binding / nuclear / 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-1J3 / ACETATE ION / Serine/threonine-protein kinase PLK1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.3 Å
AuthorsHosfield, D.J. / Skene, R.J.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2013
Title: Discovery of TAK-960: An orally available small molecule inhibitor of polo-like kinase 1 (PLK1).
Authors: Nie, Z. / Feher, V. / Natala, S. / McBride, C. / Kiryanov, A. / Jones, B. / Lam, B. / Liu, Y. / Kaldor, S. / Stafford, J. / Hikami, K. / Uchiyama, N. / Kawamoto, T. / Hikichi, Y. / ...Authors: Nie, Z. / Feher, V. / Natala, S. / McBride, C. / Kiryanov, A. / Jones, B. / Lam, B. / Liu, Y. / Kaldor, S. / Stafford, J. / Hikami, K. / Uchiyama, N. / Kawamoto, T. / Hikichi, Y. / Matsumoto, S. / Amano, N. / Zhang, L. / Hosfield, D. / Skene, R. / Zou, H. / Cao, X. / Ichikawa, T.
History
DepositionFeb 7, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 29, 2013Provider: repository / Type: Initial release
Revision 1.1Jun 5, 2013Group: Database references
Revision 1.2Nov 15, 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 1.3Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_struct_conn_angle / 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 / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _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)34,4294
Polymers33,7521
Non-polymers6773
Water2,198122
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)66.873, 66.873, 152.490
Angle α, β, γ (deg.)90.000, 90.000, 120.000
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: 33752.383 Da / Num. of mol.: 1 / Fragment: catalytic domain (UNP residues 38-330) / Mutation: T210V
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PLK1, PLK / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P53350, polo kinase
#2: Chemical ChemComp-1J3 / 4-{[(7R)-9-cyclopentyl-7-ethenyl-7-fluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl]amino}-3-methoxy-N-(4-methylpiperazin-1-yl)benzamide


Mass: 552.644 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H37FN8O3
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-ACT / ACETATE ION / Acetate


Mass: 59.044 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H3O2
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 122 / 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: 2.92 Å3/Da / Density % sol: 57.82 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 7
Details: 0.95 mM succinic acid, 1.7% PEG2000 MME, 0.4 mM zinc acetate, 100 mM HEPES, pH 7.0, VAPOR DIFFUSION, SITTING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.3 / Wavelength: 0.98 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Aug 9, 2007
RadiationMonochromator: Si(220) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 2.3→50 Å / Num. all: 18334 / Num. obs: 16203 / % possible obs: 88.4 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 1 / Redundancy: 6.3 % / Rmerge(I) obs: 0.063 / Χ2: 1.023 / Net I/σ(I): 14
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
2.3-2.353.90.2086491.015155.4
2.35-2.414.20.2036971.03157.2
2.41-2.484.40.1847570.993163.2
2.48-2.554.70.1988281.016169.9
2.55-2.634.90.1879861.027181.5
2.63-2.735.40.1711311.018195.6
2.73-2.846.50.17112061.044199.6
2.84-2.977.30.15112061.0491100
2.97-3.127.40.11212131.0311100
3.12-3.327.40.09112201.045199.9
3.32-3.577.30.07412141.0211100
3.57-3.937.10.06812391.0181100
3.93-4.570.05712471.0161100
4.5-5.676.90.04812561.0061100
5.67-506.70.0313540.998199.9

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Phasing

PhasingMethod: molecular replacement
Phasing MRRfactor: 0.41 / Cor.coef. Fo:Fc: 0.684
Highest resolutionLowest resolution
Rotation3 Å46.12 Å
Translation3 Å46.12 Å

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
MOLREPphasing
REFMACrefinement
PDB_EXTRACT3.11data extraction
HKL-2000data collection
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.3→46.16 Å / Cor.coef. Fo:Fc: 0.958 / Cor.coef. Fo:Fc free: 0.942 / WRfactor Rfree: 0.2437 / WRfactor Rwork: 0.1976 / Occupancy max: 1 / Occupancy min: 0.35 / FOM work R set: 0.7975 / SU B: 18.693 / SU ML: 0.194 / SU R Cruickshank DPI: 0.3342 / SU Rfree: 0.2397 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.334 / ESU R Free: 0.24 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2415 812 5 %RANDOM
Rwork0.1952 ---
obs0.1976 16160 88.36 %-
all-18334 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 116.08 Å2 / Biso mean: 59.7139 Å2 / Biso min: 32.67 Å2
Baniso -1Baniso -2Baniso -3
1-3.28 Å21.64 Å20 Å2
2--3.28 Å20 Å2
3----4.92 Å2
Refinement stepCycle: LAST / Resolution: 2.3→46.16 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2374 0 45 122 2541
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0192483
X-RAY DIFFRACTIONr_bond_other_d0.0010.022421
X-RAY DIFFRACTIONr_angle_refined_deg1.1832.0013353
X-RAY DIFFRACTIONr_angle_other_deg0.69635575
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.8125292
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.16222.273110
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.57315452
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.4871524
X-RAY DIFFRACTIONr_chiral_restr0.0630.2365
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0212703
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02566
LS refinement shellResolution: 2.3→2.357 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.329 39 -
Rwork0.271 688 -
all-727 -
obs--55.37 %
Refinement TLS params.Method: refined / Origin x: 39.7769 Å / Origin y: -23.1138 Å / Origin z: -15.7788 Å
111213212223313233
T0.1058 Å20.0357 Å20.0045 Å2-0.0631 Å20.0241 Å2--0.0117 Å2
L1.6012 °20.3069 °2-0.8577 °2-1.3613 °2-0.4254 °2--4.7259 °2
S0.0433 Å °-0.0415 Å °-0.0296 Å °0.1354 Å °-0.1794 Å °-0.0767 Å °0.0231 Å °0.2124 Å °0.1361 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A38 - 330
2X-RAY DIFFRACTION1A400 - 402
3X-RAY DIFFRACTION1A501 - 622

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