Artykuł w czasopiśmie
Brak miniatury
Licencja
CC-BYCC-BY - Uznanie autorstwa
 

Competition between electrostatic interactions and halogen bonding in the protein–ligand system: structural and thermodynamic studies of 5,6-dibromobenzotriazole-hCK2α complexes

Uproszczony widok
cris.lastimport.scopus2024-02-12T20:47:50Z
dc.abstract.enCK2 is a member of the CMGC group of eukaryotic protein kinases and a cancer drug target. It can be efficiently inhibited by halogenated benzotriazoles and benzimidazoles. Depending on the scaffold, substitution pattern, and pH, these compounds are either neutral or anionic. Their binding poses are dictated by a hydrophobic effect (desolvation) and a tug of war between a salt bridge/hydrogen bond (to K68) and halogen bonding (to E114 and V116 backbone oxygens). Here, we test the idea that binding poses might be controllable by pH for ligands with near-neutral pKa, using the conditionally anionic 5,6-DBBt and constitutively anionic TBBt as our models. We characterize the binding by low-volume Differential Scanning Fluorimetry (nanoDSF), Isothermal Calorimetry (ITC), Hydrogen/Deuterium eXchange (HDX), and X-ray crystallography (MX). The data indicate that the ligand pose away from the hinge dominates for the entire tested pH range (5.5–8.5). The insensitivity of the binding mode to pH is attributed to the perturbation of ligand pKa upon binding that keeps it anionic in the ligand binding pocket at all tested pH values. However, a minor population of the ligand, detectable only by HDX, shifts towards the hinge in acidic conditions. Our findings demonstrate that electrostatic (ionic) interactions predominate over halogen bonding.
dc.affiliationUniwersytet Warszawski
dc.contributor.authorCzapińska, Honorata
dc.contributor.authorPoznański, Jarosław
dc.contributor.authorBochtler, Matthias
dc.contributor.authorDadlez, Michał
dc.contributor.authorMieczkowska, Kinga
dc.contributor.authorFricke, Anna
dc.contributor.authorKaus-Drobek, Magdalena
dc.contributor.authorWiniewska-Szajewska, Maria
dc.date.accessioned2024-01-24T19:51:37Z
dc.date.available2024-01-24T19:51:37Z
dc.date.copyright2022-11-08
dc.date.issued2022
dc.description.accesstimeAT_PUBLICATION
dc.description.financeNie dotyczy
dc.description.number1
dc.description.versionFINAL_PUBLISHED
dc.description.volume12
dc.identifier.doi10.1038/S41598-022-23611-0
dc.identifier.issn2045-2322
dc.identifier.urihttps://repozytorium.uw.edu.pl//handle/item/103419
dc.identifier.weblinkhttps://www.nature.com/articles/s41598-022-23611-0.pdf
dc.languageeng
dc.pbn.affiliationphysical sciences
dc.relation.ispartofScientific Reports
dc.relation.pages18964 (1-14)
dc.rightsCC-BY
dc.sciencecloudnosend
dc.subject.plbrak
dc.titleCompetition between electrostatic interactions and halogen bonding in the protein–ligand system: structural and thermodynamic studies of 5,6-dibromobenzotriazole-hCK2α complexes
dc.typeJournalArticle
dspace.entity.typePublication