Interactions of the natural product kendomycin and the 20S proteasome

Philipp Beck; Wolfgang Heinemeyer; Anna Lena Späth; Yasser Elnakady; Rolf Müller; Michael Groll

doi:10.1016/j.jmb.2014.06.019

Interactions of the natural product kendomycin and the 20S proteasome

Philipp Beck
, Wolfgang Heinemeyer
, Anna Lena Späth
, Yasser Elnakady
, Rolf Müller
, Michael Groll

Chair of Biochemistry

Technical University of Munich
Saarland University

Research output: Contribution to journal › Article › peer-review

10 Scopus citations

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.

Original language	English
Pages (from-to)	3108-3117
Number of pages	10
Journal	Journal of Molecular Biology
Volume	426
Issue number	18
DOIs	https://doi.org/10.1016/j.jmb.2014.06.019
State	Published - 9 Sep 2014

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

X-ray crystallography
kendomycin
natural product
proteasome
sodium dodecyl sulfate

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10.1016/j.jmb.2014.06.019

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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.",

keywords = "X-ray crystallography, kendomycin, natural product, proteasome, sodium dodecyl sulfate",

author = "Philipp Beck and Wolfgang Heinemeyer and Sp{\"a}th, \{Anna Lena\} and Yasser Elnakady and Rolf M{\"u}ller and Michael Groll",

note = "Funding Information: We are grateful to R. Feicht for large-scale purification of yeast 20S proteasomes, Martin Stein for introduction to the HPLC/MS-coupled digestion assay and Eva Huber for providing PA28α. Special thanks go to Christian Dubiella for very helpful discussions. We thank the staff of the beamline X06SA at the Paul Scherer Institute, Swiss Light Source, Villigen, Switzerland for their help with data collection. M.G. and P.B. were supported by the Deutsche Forschungsgemeinschaft (SFB1035) and by the German–Israeli Foundation for Scientific Research and Development (GIF Grant 1102/2010). ",

year = "2014",

month = sep,

day = "9",

doi = "10.1016/j.jmb.2014.06.019",

language = "English",

volume = "426",

pages = "3108--3117",

journal = "Journal of Molecular Biology",

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TY - JOUR

T1 - Interactions of the natural product kendomycin and the 20S proteasome

AU - Beck, Philipp

AU - Heinemeyer, Wolfgang

AU - Späth, Anna Lena

AU - Elnakady, Yasser

AU - Müller, Rolf

AU - Groll, Michael

N1 - Funding Information: We are grateful to R. Feicht for large-scale purification of yeast 20S proteasomes, Martin Stein for introduction to the HPLC/MS-coupled digestion assay and Eva Huber for providing PA28α. Special thanks go to Christian Dubiella for very helpful discussions. We thank the staff of the beamline X06SA at the Paul Scherer Institute, Swiss Light Source, Villigen, Switzerland for their help with data collection. M.G. and P.B. were supported by the Deutsche Forschungsgemeinschaft (SFB1035) and by the German–Israeli Foundation for Scientific Research and Development (GIF Grant 1102/2010).

PY - 2014/9/9

Y1 - 2014/9/9

N2 - 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.

AB - 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.

KW - X-ray crystallography

KW - kendomycin

KW - natural product

KW - proteasome

KW - sodium dodecyl sulfate

UR - https://www.scopus.com/pages/publications/84906270220

U2 - 10.1016/j.jmb.2014.06.019

DO - 10.1016/j.jmb.2014.06.019

M3 - Article

C2 - 25038530

AN - SCOPUS:84906270220

SN - 0022-2836

VL - 426

SP - 3108

EP - 3117

JO - Journal of Molecular Biology

JF - Journal of Molecular Biology

IS - 18

ER -

Interactions of the natural product kendomycin and the 20S proteasome

Abstract

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Keywords

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