Interactions of the natural product kendomycin and the 20S proteasome |
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| Authors: | Philipp Beck,Wolfgang Heinemeyer,Anna-Lena Spä th,Yasser Elnakady,Rolf Mü ller,Michael Groll |
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| Affiliation: | 1 Center for Integrated Protein Science, Department Chemie, Lehrstuhl für Biochemie, Technische Universität München, Garching D-85747, Germany;2 Helmholtz Center for Infectious Research (HZI), Department Microbial Natural Products, Saarland University, Campus C2 3, Saarbrücken 66041, Germany |
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| 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. |
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| Keywords: | CP, core particle yCP, yeast CP KM, kendomycin FDA, Food and Drug Administration |
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