Inhibition of Eukaryotic Translation by the Antitumor Natural Product Agelastatin A

Cell Chem Biol. 2017 May 18;24(5):605-613.e5. doi: 10.1016/j.chembiol.2017.04.006. Epub 2017 Apr 27.

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.

Keywords: agelastatin A; brain cancer; chemical footprinting; drug design; marine alkaloid; molecular docking; peptidyl transferase center; rRNA seq; ribosome; translation elongation.

MeSH terms

  • Alkaloids / metabolism
  • Alkaloids / pharmacology*
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacology*
  • Biological Products / metabolism
  • Biological Products / pharmacology*
  • Dose-Response Relationship, Drug
  • HeLa Cells
  • Humans
  • Molecular Docking Simulation
  • Oxazolidinones / metabolism
  • Oxazolidinones / pharmacology*
  • Protein Biosynthesis / drug effects*
  • Protein Conformation
  • Ribosomes / drug effects
  • Ribosomes / genetics

Substances

  • Alkaloids
  • Antineoplastic Agents
  • Biological Products
  • Oxazolidinones
  • agelastatin A