Rational Design of Novel Peptidic DnaK Ligands |
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| Authors: | Markus Liebscher Dr Katja Haupt Chao Yu Dr Günther Jahreis Dr Christian Lücke Dr Cordelia Schiene‐Fischer Dr |
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| Affiliation: | 1. Max Planck Research Unit for Enzymology of Protein Folding, Weinbergweg 22, 06120 Halle (Saale) (Germany), Fax: (+49)?345‐5511972;2. Present address: Nuffield Department of Clinical Medicine, Room 7506, John Radcliffe Hospital, Headington, Oxford, OX3 9DU (UK) |
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| 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 1H/15N‐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 μM . |
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| Keywords: | antibacterial agents apiase combinatorial chemistry inhibitors pyrrhocoricin |
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