Structural Adaptation of the Single-Stranded DNA-Binding Protein C-Terminal to DNA Metabolizing Partners Guides Inhibitor Design.

Autor: Tököli A; Department of Medical Chemistry, University of Szeged, H6720 Szeged, Hungary., Bodnár B; Department of Medical Chemistry, University of Szeged, H6720 Szeged, Hungary.; ELKH-SZTE Biomimetic Systems Research Group, Eötvös Loránd Research Network (ELKH), H6720 Szeged, Hungary., Bogár F; ELKH-SZTE Biomimetic Systems Research Group, Eötvös Loránd Research Network (ELKH), H6720 Szeged, Hungary., Paragi G; Department of Medical Chemistry, University of Szeged, H6720 Szeged, Hungary.; Institute of Physics, University of Pécs, H7624 Pécs, Hungary.; Department of Theoretical Physics, University of Szeged, H6720 Szeged, Hungary., Hetényi A; Department of Medical Chemistry, University of Szeged, H6720 Szeged, Hungary., Bartus É; Department of Medical Chemistry, University of Szeged, H6720 Szeged, Hungary.; ELKH-SZTE Biomimetic Systems Research Group, Eötvös Loránd Research Network (ELKH), H6720 Szeged, Hungary., Wéber E; Department of Medical Chemistry, University of Szeged, H6720 Szeged, Hungary.; ELKH-SZTE Biomimetic Systems Research Group, Eötvös Loránd Research Network (ELKH), H6720 Szeged, Hungary., Hegedüs Z; Department of Medical Chemistry, University of Szeged, H6720 Szeged, Hungary., Szabó Z; Department of Medical Chemistry, University of Szeged, H6720 Szeged, Hungary., Kecskeméti G; Department of Medical Chemistry, University of Szeged, H6720 Szeged, Hungary., Szakonyi G; Institute of Pharmaceutical Analysis, University of Szeged, H6720 Szeged, Hungary., Martinek TA; Department of Medical Chemistry, University of Szeged, H6720 Szeged, Hungary.; ELKH-SZTE Biomimetic Systems Research Group, Eötvös Loránd Research Network (ELKH), H6720 Szeged, Hungary.
Jazyk: angličtina
Zdroj: Pharmaceutics [Pharmaceutics] 2023 Mar 23; Vol. 15 (4). Date of Electronic Publication: 2023 Mar 23.
DOI: 10.3390/pharmaceutics15041032
Abstrakt: Single-stranded DNA-binding protein (SSB) is a bacterial interaction hub and an appealing target for antimicrobial therapy. Understanding the structural adaptation of the disordered SSB C-terminus (SSB-Ct) to DNA metabolizing enzymes (e.g., ExoI and RecO) is essential for designing high-affinity SSB mimetic inhibitors. Molecular dynamics simulations revealed the transient interactions of SSB-Ct with two hot spots on ExoI and RecO. The residual flexibility of the peptide-protein complexes allows adaptive molecular recognition. Scanning with non-canonical amino acids revealed that modifications at both termini of SSB-Ct could increase the affinity, supporting the two-hot-spot binding model. Combining unnatural amino acid substitutions on both segments of the peptide resulted in enthalpy-enhanced affinity, accompanied by enthalpy-entropy compensation, as determined by isothermal calorimetry. NMR data and molecular modeling confirmed the reduced flexibility of the improved affinity complexes. Our results highlight that the SSB-Ct mimetics bind to the DNA metabolizing targets through the hot spots, interacting with both of segments of the ligands.
Databáze: MEDLINE
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