Journal Article

PUBDB-2023-00181

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Competition between electrostatic interactions and halogen bonding in the protein–ligand system: structural and thermodynamic studies of 5,6-dibromobenzotriazole-hCK2$α$ complexes

Winiewska-Szajewska, M. (Corresponding author) ; Czapinska, H.Extern*EMBL* ; Kaus-Drobek, M. ; Fricke, A. ; Mieczkowska, K. ; Dadlez, M. ; Bochtler, M.Extern* ; Poznański, J. (Corresponding author)

2022
Macmillan Publishers Limited, part of Springer Nature [London]

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Please use a persistent id in citations: doi:10.1038/s41598-022-23611-0  doi:10.3204/PUBDB-2023-00181

Abstract: CK2 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 pK$_a$, 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 pK$_a$ 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.

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Contributing Institute(s):

1. DOOR-User (DOOR ; HAS-User)
2. EMBL (EMBL)

Research Program(s):

1. 6G3 - PETRA III (DESY) (POF4-6G3) (POF4-6G3)
2. BIOSTRUCT-X - Transnational access and enhancement of integrated Biological Structure determination at synchrotron X-ray radiation facilities (283570) (283570)

Experiment(s):

1. PETRA Beamline P11 (PETRA III)
2. PETRA Beamline P14 (PETRA III)

Appears in the scientific report 2022

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