Interactions of the natural product kendomycin and the 20S proteasome

Journal of Molecular Biology, 2014, doi:10.1016/j.jmb.2014.06.019, Volume 426, Issue 18, Pages 3108–3117 published on 09.09.2014
Journal of Molecular Biology, online article
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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