Inhibition of Eukaryotic Translation by the Antitumor Natural Product Agelastatin A

Brandon McClary, Boris Zinshteyn, Mélanie Meyer, Morgan Jouanneau, Simone Pellegrino, Gulnara Yusupova, Anthony Schuller, Jeremy Chris P. Reyes, Junyan Lu, Zufeng Guo, Safiat Ayinde, Cheng Luo, Yongjun Dang, Daniel Romo, Marat Yusupov, Rachel Green, Jun Liu

Research output: Contribution to journalArticle

Abstract

Protein synthesis plays an essential role in cell proliferation, differentiation, and survival. Inhibitors of eukaryotic translation have entered the clinic, establishing the translation machinery as a promising target for chemotherapy. A recently discovered, structurally unique marine sponge-derived brominated alkaloid, (-)-agelastatin A (AglA), possesses potent antitumor activity. Its underlying mechanism of action, however, has remained unknown. Using a systematic top-down approach, we show that AglA selectively inhibits protein synthesis. Using a high-throughput chemical footprinting method, we mapped the AglA-binding site to the ribosomal A site. A 3.5 Å crystal structure of the 80S eukaryotic ribosome from S. cerevisiae in complex with AglA was obtained, revealing multiple conformational changes of the nucleotide bases in the ribosome accompanying the binding of AglA. Together, these results have unraveled the mechanism of inhibition of eukaryotic translation by AglA at atomic level, paving the way for future structural modifications to develop AglA analogs into novel anticancer agents. The natural product AglA possesses promising antitumor activity. But its mechanism of action has remained a mystery. McClary et al. identified the A site of the ribosome as the molecular target of AglA, elucidating its molecular mechanism of action.

Original languageEnglish (US)
JournalCell Chemical Biology
DOIs
Publication statusAccepted/In press - Dec 18 2016

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Keywords

  • Agelastatin A
  • Brain cancer
  • Chemical footprinting
  • Drug design
  • Marine alkaloid
  • Molecular docking
  • Peptidyl transferase center
  • Ribosome
  • RRNA seq
  • Translation elongation

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Molecular Biology
  • Molecular Medicine
  • Drug Discovery
  • Pharmacology

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