| Autor: |
Kirschner H; Biochemistry II, Biomolecular NMR Spectroscopy, RUBiospec|NMR, and PhenomeCentre@RUBUAR, Faculty of Chemistry and Biochemistry, Ruhr University Bochum, Universitätsstraße 150, Bochum 44801, Germany., Heister N; Biochemistry II, Biomolecular NMR Spectroscopy, RUBiospec|NMR, and PhenomeCentre@RUBUAR, Faculty of Chemistry and Biochemistry, Ruhr University Bochum, Universitätsstraße 150, Bochum 44801, Germany., Zouatom M; Faculty of Mathematics and Natural Sciences, Bioorganic Chemistry, University of Wuppertal, Gaußstraße 20, Wuppertal 42119, Germany., Zhou T; Faculty of Mathematics and Natural Sciences, Bioorganic Chemistry, University of Wuppertal, Gaußstraße 20, Wuppertal 42119, Germany., Hofmann E; Protein Crystallography, Faculty of Biology and Biotechnology, Ruhr University Bochum, Universitätsstraße 150, Bochum 44801, Germany., Scherkenbeck J; Faculty of Mathematics and Natural Sciences, Bioorganic Chemistry, University of Wuppertal, Gaußstraße 20, Wuppertal 42119, Germany., Stoll R; Biochemistry II, Biomolecular NMR Spectroscopy, RUBiospec|NMR, and PhenomeCentre@RUBUAR, Faculty of Chemistry and Biochemistry, Ruhr University Bochum, Universitätsstraße 150, Bochum 44801, Germany. |
| Abstrakt: |
Peptide deformylase (PDF) is involved in bacterial protein maturation processes. Originating from the interest in a new antibiotic, tremendous effort was put into the refinement of PDF inhibitors (PDFIs) and their selectivity. We obtained a full NMR backbone assignment the emergent additional protein backbone resonances of ecPDF 1-147 in complex with 2-(5-bromo-1 H -indol-3-yl)- N -hydroxyacetamide ( 2 ), a potential new structural scaffold for more selective PDFIs. We also determined the complex crystal structures of E. coli PDF (ecPDF fl) and 2 . Our structure suggests an alternative ligand conformation within the protein, a possible starting point for further selectivity optimization. The orientation of the second ligand conformation in the crystal structure points toward a small region of the S1' pocket, which differs between bacterial PDFs and human PDF. Moreover, we analyzed the binding mode of 2 via NMR TITAN line shape analysis, revealing an induced fit mechanism. |
