Interactions of the natural product kendomycin and the 20S proteasome

, By:Beck, P ; Heinemeyer, W ; Spath, AL ; Elnakady, Y ; Muller, R; Groll, M . 2014

Abstract

Natural products are a valuable source for novel lead structures in drug discovery, but for the majority of isolated bioactive compounds, the cellular targets are unknown. The structurally unique ansa-polyketide kendomycin (KM) was reported to exert its potent cytotoxic effects via impairment of the ubiquitin proteasome system, but the exact mode of action remained unclear. Here, we present a systematic biochemical characterization of KM-proteasome interactions in vitro and in vivo, including complex structures of wild type and mutant yeast 20S proteasome with KM. Our results provide evidence for a polypharmacological mode of action for KM's cytotoxic effect on cancer cells. (C) 2014 Elsevier Ltd. All rights reserved.

Volume Number

426

Issue Number

Magazine \ Newspaper

JOURNAL OF MOLECULAR BIOLOGY

Pages

3108-3117

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