Interactions of the natural product kendomycin and the 20S proteasome

• KM blocks proteasome activity in the presence of SDS.
• Cocrystal structure of yeast 20S proteasome and KM shows novel binding mode.
• KM binds to the proteasome at an exo-site between subunits β2 and β7′.
• Allosteric effect is not observed.
• Rapid cytotoxic effect of KM due to polypharmacological mode of action, not proteasome inhibition.

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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