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Halogen Atoms in the Protein–Ligand System. Structural and Thermodynamic Studies of the Binding of Bromobenzotriazoles by the Catalytic Subunit of Human Protein Kinase CK2

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dc.abstract.enBinding of a family of brominated benzotriazoles to the catalytic subunit of human protein kinase CK2 (hCK2 alpha) was used as a model system to assess the contribution of halogen bonding to protein-ligand interaction. CK2 is a constitutively active pleiotropic serine/threonine protein kinase that belongs to the CMGC group of eukaryotic protein kinases (EPKs). Due to the addiction of some cancer cells, CK2 is an attractive and well-characterized drug target. Halogenated benzotriazoles act as ATP-competitive inhibitors with unexpectedly good selectivity for CK2 over other EPKs. We have characterized the interaction of bromobenzotriazoles with hCK2 alpha by X-ray crystallography, low-volume differential scanning fluorimetry, and isothermal titration calorimetry. Properties of free ligands in solution were additionally characterized by volumetric and RT-HPLC measurements. Thermodynamic data indicate that the affinity increases with bromo substitution, with greater contributions from 5- and 6-substituents than 4- and 7-substituents. Except for 4,7-disubstituted compounds, the bromobenzotriazoles adopt a canonical pose with the triazole close to lysine 68, which precludes halogen bonding. More highly substituted benzotriazoles adopt many additional noncanonical poses, presumably driven by a large hydrophobic contribution to binding. Some noncanonical ligand orientations allow the formation of halogen bonds with the hinge region. Consistent with a predominantly hydrophobic interaction, the isobaric heat capacity decreases upon ligand binding, the more so the higher the substitution.
dc.affiliationUniwersytet Warszawski
dc.contributor.authorCzapińska, Honorata
dc.contributor.authorSzymaniec-Rutkowska, Anna
dc.contributor.authorPiasecka, Anna
dc.contributor.authorPoznański, Jarosław
dc.contributor.authorWiniewska-Szajewska, Maria
dc.contributor.authorBochtler, Matthias
dc.date.accessioned2024-01-25T02:54:50Z
dc.date.available2024-01-25T02:54:50Z
dc.date.copyright2021-03-09
dc.date.issued2021
dc.description.accesstimeBEFORE_PUBLICATION
dc.description.financeNie dotyczy
dc.description.number10
dc.description.versionFINAL_PUBLISHED
dc.description.volume125
dc.identifier.doi10.1021/ACS.JPCB.0C10264
dc.identifier.issn1520-6106
dc.identifier.urihttps://repozytorium.uw.edu.pl//handle/item/108270
dc.identifier.weblinkhttps://pubs.acs.org/doi/pdf/10.1021/acs.jpcb.0c10264
dc.languageeng
dc.pbn.affiliationphysical sciences
dc.relation.ispartofJournal of Physical Chemistry B
dc.relation.pages2491-2503
dc.rightsCC-BY
dc.sciencecloudnosend
dc.titleHalogen Atoms in the Protein–Ligand System. Structural and Thermodynamic Studies of the Binding of Bromobenzotriazoles by the Catalytic Subunit of Human Protein Kinase CK2
dc.typeJournalArticle
dspace.entity.typePublication