Rational design of novel peptidic DnaK ligands

Chembiochem : a European Journal of Chemical Biology
Markus LiebscherCordelia Schiene-Fischer

Abstract

The hsp70 chaperone DnaK from E. coli plays a major role in cellular stress response and is involved in assisted protein folding in vivo. By screening a combinatorial peptide library, we identified several DnaK-specific peptide ligands with nanomolar affinities, which are able to inhibit the secondary amide peptide bond cis/trans isomerase (APIase) activity of DnaK, as well as DnaK/DnaJ/GrpE-assisted refolding of firefly luciferase. Our designed DnaK inhibitors have the capability to penetrate E. coli cells and feature a high protease resistance. Once inside the cell, they physically target DnaK. NMR-based (1)H/(15)N-HSQC experiments furthermore confirmed that the designed peptidic ligands all bind in an identical manner to the conventional peptide-binding site of DnaK. The subsequent blocking of DnaK function apparently results in the observed antibacterial effects on E. coli cells, with minimum inhibitory concentrations in the range of 100 microM.

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Citations

May 10, 2012·Analytical and Bioanalytical Chemistry·K DobslaffT Zuchner
May 5, 2011·Chembiochem : a European Journal of Chemical Biology·Yanyan HuangYi Chen
Apr 9, 2013·Bioorganic & Medicinal Chemistry Letters·Meilan HuangRichard Kennedy
Dec 28, 2010·International Journal of Antimicrobial Agents·Daniel KnappeRalf Hoffmann
Apr 9, 2013·Journal of Molecular Biology·Michael ZahnNorbert Sträter
Dec 30, 2020·Journal of Global Antimicrobial Resistance·Ann-Kathrin KriegerChristoph Georg Baums
Apr 25, 2020·Biochemistry·Matthew D DalphinSilvia Cavagnero

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