Inhibition of eukaryotic translation elongation by the antitumor natural product Mycalamide B

Yongjun Dang, Tilman Schneider-Poetsch, Daniel E. Eyler, John C. Jewett, Shridhar Bhat, Viresh H. Rawal, Rachel Green, Jun O. Liu

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

Mycalamide B (MycB) is a marine sponge-derived natural product with potent antitumor activity. Although it has been shown to inhibit protein synthesis, the molecular mechanism of action by MycB remains incompletely understood. We verified the inhibition of translation elongation by in vitro HCV IRES dual luciferase assays, ribosome assembly, and in vivo [ 35S]methinione labeling experiments. Similar to cycloheximide (CHX), MycB inhibits translation elongation through blockade of eEF2-mediated translocation without affecting the eEF1A-mediated loading of tRNA onto the ribosome, AUG recognition, or dipeptide synthesis. Using chemical footprinting, we identified the MycB binding site proximal to the C3993 28S rRNA residue on the large ribosomal subunit. However, there are also subtle, but significant differences in the detailed mechanisms of action of MycB and CHX. First, MycB arrests the ribosome on the mRNA one codon ahead of CHX. Second, MycB specifically blocked tRNA binding to the E-site of the large ribosomal subunit. Moreover, they display different polysome profiles in vivo. Together, these observations shed new light on the mechanism of inhibition of translation elongation by MycB. Published by Cold Spring Harbor Laboratory Press.

Original languageEnglish (US)
Pages (from-to)1578-1588
Number of pages11
JournalRNA
Volume17
Issue number8
DOIs
StatePublished - Aug 2011
Externally publishedYes

Keywords

  • Eukaryotic ribosome
  • Mycalamide B
  • Translation elongation
  • tRNA

ASJC Scopus subject areas

  • Molecular Biology

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