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- PDB-4b6l: Discovery of Oral Polo-Like Kinase (PLK) Inhibitors with Enhanced... -

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Basic information

Entry
Database: PDB / ID: 4b6l
TitleDiscovery of Oral Polo-Like Kinase (PLK) Inhibitors with Enhanced Selectivity Profile using Residue Targeted Drug Design
ComponentsSERINE/THREONINE-PROTEIN KINASE PLK3
KeywordsTRANSFERASE / KINASE INHIBITORS / WATER-MEDIATED H-BOND
Function / homology
Function and homology information


mitotic G1/S transition checkpoint signaling / positive regulation of chaperone-mediated autophagy / endomitotic cell cycle / Golgi disassembly / polo kinase / positive regulation of intracellular protein transport / Golgi stack / TP53 regulates transcription of additional cell cycle genes whose exact role in the p53 pathway remain uncertain / response to osmotic stress / regulation of cell division ...mitotic G1/S transition checkpoint signaling / positive regulation of chaperone-mediated autophagy / endomitotic cell cycle / Golgi disassembly / polo kinase / positive regulation of intracellular protein transport / Golgi stack / TP53 regulates transcription of additional cell cycle genes whose exact role in the p53 pathway remain uncertain / response to osmotic stress / regulation of cell division / cytoplasmic microtubule organization / negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / regulation of cytokinesis / regulation of signal transduction by p53 class mediator / mitotic spindle organization / response to reactive oxygen species / response to radiation / kinetochore / G1/S transition of mitotic cell cycle / spindle pole / G2/M transition of mitotic cell cycle / p53 binding / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / Regulation of TP53 Activity through Phosphorylation / protein phosphorylation / protein serine kinase activity / protein serine/threonine kinase activity / neuronal cell body / apoptotic process / centrosome / dendrite / DNA damage response / negative regulation of apoptotic process / nucleolus / negative regulation of transcription by RNA polymerase II / nucleoplasm / ATP binding / nucleus / cytoplasm
Similarity search - Function
Serine/threonine-protein kinase PLK3, 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 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 ...Serine/threonine-protein kinase PLK3, 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 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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-9ZP / Serine/threonine-protein kinase PLK3
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MIR / Resolution: 1.9 Å
AuthorsBrown, K. / Charrier, J.D. / Durrant, S. / Griffiths, M. / Hudson, C. / Kay, D. / Knegtel, R. / ODonnell, M. / Pierard, F. / Twin, H. ...Brown, K. / Charrier, J.D. / Durrant, S. / Griffiths, M. / Hudson, C. / Kay, D. / Knegtel, R. / ODonnell, M. / Pierard, F. / Twin, H. / Weber, P. / Young, S.
CitationJournal: To be Published
Title: Discovery of Oral Polo-Like Kinase (Plk) Inhibitors with Enhanced Selectivity Profile Using Residue Targeted Drug Design
Authors: Brown, K. / Charrier, J.D. / Durrant, S. / Griffiths, M. / Hudson, C. / Kay, D. / Knegtel, R. / Odonnell, M. / Pierard, F. / Twin, H. / Weber, P. / Young, S.
History
DepositionAug 14, 2012Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 21, 2013Provider: repository / Type: Initial release
Revision 1.1May 8, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _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 PLK3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,7913
Polymers32,2181
Non-polymers5732
Water4,107228
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)144.140, 56.370, 45.320
Angle α, β, γ (deg.)90.00, 96.83, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-2115-

HOH

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Components

#1: Protein SERINE/THREONINE-PROTEIN KINASE PLK3 / POLO-LIKE KINASE 3 / CYTOKINE-INDUCIBLE SERINE/THREONINE-PROTEIN KINASE / FGF-INDUCIBLE KINASE / ...POLO-LIKE KINASE 3 / CYTOKINE-INDUCIBLE SERINE/THREONINE-PROTEIN KINASE / FGF-INDUCIBLE KINASE / POLO-LIKE KINASE 3 / PLK-3 / PROLIFERATION-RELATED KINASE


Mass: 32218.236 Da / Num. of mol.: 1 / Fragment: CATALYTIC KINASE DOMAIN, RESIDUES 52-332
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: SPODOPTERA FRUGIPERDA (fall armyworm) / References: UniProt: Q9H4B4, polo kinase
#2: Chemical ChemComp-9ZP / 4-[[(4R)-5-cyclopentyl-4-ethyl-3a,4-dihydro-3H-[1,2,4]triazolo[4,3-f]pteridin-7-yl]amino]-N-cyclopropyl-3-methoxy-benzamide


Mass: 476.574 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H32N8O2
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 228 / 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: 2.57 Å3/Da / Density % sol: 50 % / Description: NONE
Crystal growDetails: 0.8M NAH2PO4, 1.2M K2HPO4, 0.1M MES PH 5.2, 10MM DTT

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SRS / Beamline: PX9.5 / Wavelength: 1.488
DetectorType: ADSC QUANTUM 4 / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.488 Å / Relative weight: 1
ReflectionResolution: 1.8→44 Å / Num. obs: 27438 / % possible obs: 92.9 % / Observed criterion σ(I): 3 / Redundancy: 1.6 % / Biso Wilson estimate: 38.77 Å2 / Rmerge(I) obs: 0.03 / Net I/σ(I): 13.1
Reflection shellResolution: 1.9→2 Å / Redundancy: 1.4 % / Rmerge(I) obs: 0.69 / Mean I/σ(I) obs: 1 / % possible all: 74.7

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Processing

Software
NameVersionClassification
BUSTER2.11.2refinement
MOSFLMdata reduction
SCALAdata scaling
AMoREphasing
RefinementMethod to determine structure: MIR
Starting model: NONE

Resolution: 1.9→23.88 Å / Cor.coef. Fo:Fc: 0.8946 / Cor.coef. Fo:Fc free: 0.8644 / SU R Cruickshank DPI: 0.189 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.194 / SU Rfree Blow DPI: 0.177 / SU Rfree Cruickshank DPI: 0.175
Details: IDEAL-DIST CONTACT TERM CONTACT SETUP. ALL ATOMS HAVE CCP4 ATOM TYPE FROM LIBRARY
RfactorNum. reflection% reflectionSelection details
Rfree0.2889 1327 5.04 %RANDOM
Rwork0.2443 ---
obs0.2465 26307 92.01 %-
Displacement parametersBiso mean: 45.5 Å2
Baniso -1Baniso -2Baniso -3
1-8.8985 Å20 Å2-9.6216 Å2
2---18.1837 Å20 Å2
3---9.2852 Å2
Refine analyzeLuzzati coordinate error obs: 0.405 Å
Refinement stepCycle: LAST / Resolution: 1.9→23.88 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2269 0 40 228 2537
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012369HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.143213HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d819SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes46HARMONIC2
X-RAY DIFFRACTIONt_gen_planes345HARMONIC5
X-RAY DIFFRACTIONt_it2369HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.05
X-RAY DIFFRACTIONt_other_torsion17.15
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion297SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact3169SEMIHARMONIC4
LS refinement shellResolution: 1.9→1.98 Å / Total num. of bins used: 13
RfactorNum. reflection% reflection
Rfree0.5993 95 4.22 %
Rwork0.4713 2156 -
all0.4764 2251 -
obs--92.01 %
Refinement TLS params.Method: refined / Origin x: 51.4489 Å / Origin y: 1.9461 Å / Origin z: 1.6916 Å
111213212223313233
T0.0371 Å20.0044 Å2-0.0553 Å2--0.0684 Å20.0076 Å2---0.0707 Å2
L1.425 °20.2925 °2-0.1649 °2-0.4024 °2-0.0846 °2--1.0174 °2
S-0.0047 Å °-0.1055 Å °-0.042 Å °-0.029 Å °0.015 Å °0.0071 Å °0.0245 Å °0.0355 Å °-0.0103 Å °
Refinement TLS groupSelection details: CHAIN A

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