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- PDB-4i5m: Selective & Brain-Permeable Polo-like Kinase-2 (Plk-2) Inhibitors... -

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Basic information

Entry
Database: PDB / ID: 4i5m
TitleSelective & Brain-Permeable Polo-like Kinase-2 (Plk-2) Inhibitors that Reduce -Synuclein Phosphorylation in Rat Brain
ComponentsSerine/threonine-protein kinase PLK2
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Polo-like kinase-2 (Plk-2) / Synuclein / Parkinson's disease / Kinase Inhibitor / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


regulation of centriole replication / Rap protein signal transduction / negative regulation of apoptotic process in bone marrow cell / polo kinase / ATP-dependent protein binding / long-term synaptic depression / TP53 regulates transcription of additional cell cycle genes whose exact role in the p53 pathway remain uncertain / CD163 mediating an anti-inflammatory response / positive regulation of cell migration involved in sprouting angiogenesis / negative regulation of cellular senescence ...regulation of centriole replication / Rap protein signal transduction / negative regulation of apoptotic process in bone marrow cell / polo kinase / ATP-dependent protein binding / long-term synaptic depression / TP53 regulates transcription of additional cell cycle genes whose exact role in the p53 pathway remain uncertain / CD163 mediating an anti-inflammatory response / positive regulation of cell migration involved in sprouting angiogenesis / negative regulation of cellular senescence / positive regulation of autophagy / DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest / NPAS4 regulates expression of target genes / centriole / negative regulation of angiogenesis / mitotic spindle organization / long-term synaptic potentiation / negative regulation of inflammatory response to antigenic stimulus / regulation of synaptic plasticity / kinetochore / memory / spindle pole / positive regulation of protein catabolic process / G1/S transition of mitotic cell cycle / peptidyl-serine phosphorylation / positive regulation of canonical NF-kappaB signal transduction / Ras protein signal transduction / protein phosphorylation / protein serine kinase activity / protein serine/threonine kinase activity / centrosome / dendrite / chromatin / negative regulation of apoptotic process / ATP binding / nucleus / cytosol / cytoplasm
Similarity search - Function
PLK2, 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 ...PLK2, 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-R78 / Serine/threonine-protein kinase PLK2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.801 Å
AuthorsAubele, D.L. / Hom, R.K. / Adler, M. / Galemmo Jr., R.A. / Bowers, S. / Truong, A.P. / Pan, H. / Beroza, P. / Neitz, R.J. / Yao, N. ...Aubele, D.L. / Hom, R.K. / Adler, M. / Galemmo Jr., R.A. / Bowers, S. / Truong, A.P. / Pan, H. / Beroza, P. / Neitz, R.J. / Yao, N. / Lin, M. / Tonn, G. / Zhang, H. / Bova, M.P. / Ren, Z. / Tam, D. / Ruslim, L. / Baker, J. / Diep, L. / Fitzgerald, K. / Hoffman, J. / Motter, R. / Fauss, D. / Tanaka, P. / Dappen, M. / Jagodzinski, J. / Chan, W. / Konradi, A.W. / Latimer, L. / Zhu, Y.L. / Artis, D.R. / Sham, H.L. / Anderson, J.P. / Bergeron, M.
CitationJournal: Chemmedchem / Year: 2013
Title: Selective and brain-permeable polo-like kinase-2 (Plk-2) inhibitors that reduce alpha-synuclein phosphorylation in rat brain.
Authors: Aubele, D.L. / Hom, R.K. / Adler, M. / Galemmo, R.A. / Bowers, S. / Truong, A.P. / Pan, H. / Beroza, P. / Neitz, R.J. / Yao, N. / Lin, M. / Tonn, G. / Zhang, H. / Bova, M.P. / Ren, Z. / Tam, ...Authors: Aubele, D.L. / Hom, R.K. / Adler, M. / Galemmo, R.A. / Bowers, S. / Truong, A.P. / Pan, H. / Beroza, P. / Neitz, R.J. / Yao, N. / Lin, M. / Tonn, G. / Zhang, H. / Bova, M.P. / Ren, Z. / Tam, D. / Ruslim, L. / Baker, J. / Diep, L. / Fitzgerald, K. / Hoffman, J. / Motter, R. / Fauss, D. / Tanaka, P. / Dappen, M. / Jagodzinski, J. / Chan, W. / Konradi, A.W. / Latimer, L. / Zhu, Y.L. / Sham, H.L. / Anderson, J.P. / Bergeron, M. / Artis, D.R.
History
DepositionNov 28, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 25, 2013Provider: repository / Type: Initial release
Revision 1.1Oct 8, 2014Group: Structure summary
Revision 1.2Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / 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_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 PLK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,3542
Polymers35,8321
Non-polymers5221
Water4,828268
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)104.329, 60.217, 53.213
Angle α, β, γ (deg.)90.00, 107.40, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-610-

HOH

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Components

#1: Protein Serine/threonine-protein kinase PLK2 / Polo-like kinase 2 / PLK-2 / hPlk2 / Serine/threonine-protein kinase SNK / hSNK / Serum-inducible kinase


Mass: 35832.188 Da / Num. of mol.: 1 / Fragment: PLK2 kinase domain / Mutation: C83S, V87T, A119S, A216S, C259A, C291S, L335T
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PLK2, SNK / Production host: Escherichia coli (E. coli) / References: UniProt: Q9NYY3, polo kinase
#2: Chemical ChemComp-R78 / 4-{[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl]amino}-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide


Mass: 521.654 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H39N7O3
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 268 / 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: 2.23 Å3/Da / Density % sol: 44.74 %
Crystal growTemperature: 277 K / Method: evaporation / pH: 5.5
Details: 0.1 M Bis-Tris pH 5.5, 0.8 M sodium formate, 19% PEG 3350, EVAPORATION, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 0.9788 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jan 30, 2010
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9788 Å / Relative weight: 1
ReflectionResolution: 1.801→40 Å / Num. all: 31632 / Num. obs: 29562 / % possible obs: 92.6 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 1
Reflection shellResolution: 1.801→1.847 Å / % possible all: 46.8

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Processing

Software
NameVersionClassification
HKL-2000data collection
AMoREphasing
REFMAC5.2.0019refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.801→39.34 Å / Cor.coef. Fo:Fc: 0.891 / Cor.coef. Fo:Fc free: 0.818 / SU B: 9.697 / SU ML: 0.292 / Cross valid method: THROUGHOUT / ESU R: 0.242 / ESU R Free: 0.245 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.39202 1279 5.1 %RANDOM
Rwork0.3199 ---
all0.32356 30632 --
obs0.32356 24042 86.48 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 30.701 Å2
Baniso -1Baniso -2Baniso -3
1--0.03 Å20 Å2-0.02 Å2
2--0 Å20 Å2
3---0.02 Å2
Refinement stepCycle: LAST / Resolution: 1.801→39.34 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2227 0 38 268 2533
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0222322
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.3451.9863134
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.3225271
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.95122.523107
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.65515417
X-RAY DIFFRACTIONr_dihedral_angle_4_deg10.8051520
X-RAY DIFFRACTIONr_chiral_restr0.1020.2336
X-RAY DIFFRACTIONr_gen_planes_refined0.0020.021742
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.2070.21294
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined0.3030.21550
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1050.2200
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1910.287
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1840.227
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.801→1.847 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.51 56 -
Rwork0.377 947 -
obs--46.8 %

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