title: Interactions of the natural product kendomycin and the 20S proteasome.
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.
authors.affiliation: Center for Integrated Protein Science, Department Chemie, Lehrstuhl für Biochemie, Technische Universität München, Garching D-85747, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Beck
authors.affiliation: Center for Integrated Protein Science, Department Chemie, Lehrstuhl für Biochemie, Technische Universität München, Garching D-85747, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Heinemeyer
authors.affiliation: Center for Integrated Protein Science, Department Chemie, Lehrstuhl für Biochemie, Technische Universität München, Garching D-85747, Germany.
authors.forename: Anna-Lena
authors.initials: AL
authors.lastname: Späth
authors.affiliation: Helmholtz Center for Infectious Research (HZI), Department Microbial Natural Products, Saarland University, Campus C2 3, Saarbrücken 66041, Germany.
authors.forename: Yasser
authors.initials: Y
authors.lastname: Elnakady
authors.affiliation: Helmholtz Center for Infectious Research (HZI), Department Microbial Natural Products, Saarland University, Campus C2 3, Saarbrücken 66041, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Müller
authors.affiliation: Center for Integrated Protein Science, Department Chemie, Lehrstuhl für Biochemie, Technische Universität München, Garching D-85747, Germany. Electronic address: michael.groll@tum.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Groll
mesh_terms: D001688:Biological Products / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D018360:Crystallography, X-Ray; D003593:Cytoplasm / Q000378:metabolism; D005260:Female; D006367:HeLa Cells; D006801:Humans; D007700:Kinetics; D013058:Mass Spectrometry; D008958:Models, Molecular; D009154:Mutation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D011485:Protein Binding; D017828:Rifabutin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D001688:Biological Products; D061988:Proteasome Inhibitors; D025801:Ubiquitin; C485395:kendomycin; D017828:Rifabutin; D046988:Proteasome Endopeptidase Complex
keywords: X-ray crystallography; kendomycin; natural product; proteasome; sodium dodecyl sulfate