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Rational drug-design approach supported with thermodynamic studies — a peptide leader for the efficient bi-substrate inhibitor of protein kinase CK2.

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dc.abstract.enNumerous inhibitors of protein kinases act on the basis of competition, targeting the ATP binding site. In this work, we present a procedure of rational design of a bi-substrate inhibitor, complemented with biophysical assays. The inhibitors of this type are commonly engineered by combining ligands carrying an ATP-like part with a peptide or peptide-mimicking fragment that determines specificity. Approach presented in this paper led to generation of a specific system for independent screening for efficient ligands and peptides, by means of thermodynamic measurements, that assessed the ability of the identified ligand and peptide to combine into a bi-substrate inhibitor. The catalytic subunit of human protein kinase CK2 was used as the model target. Peptide sequence was optimized using peptide libraries [KGDE]-[DE]-[ST]-[DE]3–4-NH2, originated from the consensus CK2 sequence. We identified KESEEE-NH2 peptide as the most promising one, whose binding affinity is substantially higher than that of the reference RRRDDDSDDD peptide. We assessed its potency to form an efficient bi-substrate inhibitor using tetrabromobenzotriazole (TBBt) as the model ATP-competitive inhibitor. The formation of ternary complex was monitored using Differential Scanning Fluorimetry (DSF), Microscale Thermophoresis (MST) and Isothermal Titration Calorimetry (ITC).
dc.affiliationUniwersytet Warszawski
dc.contributor.authorPoznański, Jarosław
dc.contributor.authorPłonka, Dawid
dc.contributor.authorWiniewska-Szajewska, Maria
dc.contributor.authorŻukow, Igor
dc.date.accessioned2024-01-25T18:46:49Z
dc.date.available2024-01-25T18:46:49Z
dc.date.copyright2019-07-29
dc.date.issued2019
dc.description.accesstimeAT_PUBLICATION
dc.description.financeNie dotyczy
dc.description.numberbrak
dc.description.versionFINAL_AUTHOR
dc.description.volume9
dc.identifier.doi10.1038/S41598-019-47404-0
dc.identifier.issn2045-2322
dc.identifier.urihttps://repozytorium.uw.edu.pl//handle/item/117883
dc.identifier.weblinkhttps://www.nature.com/articles/s41598-019-47404-0
dc.languageeng
dc.pbn.affiliationphysical sciences
dc.relation.ispartofScientific Reports
dc.relation.pages11018
dc.rightsCC-BY
dc.sciencecloudnosend
dc.subject.plbrak
dc.titleRational drug-design approach supported with thermodynamic studies — a peptide leader for the efficient bi-substrate inhibitor of protein kinase CK2.
dc.typeJournalArticle
dspace.entity.typePublication