Inhibition of Eukaryotic Translation by the Antitumor Natural Product Agelastatin A

Abstract

SUMMARY 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 Amaryllidaceae Alkaloid Haemanthamine Binds the Eukaryotic Ribosome to Repress Cancer Cell Growth

“…The drug is placed at a distance of approximately 3 Å from the amino acid backbone and blocks the access of bulky or long side chains in the A-site cleft ( Figure S3A), thereby hindering peptide bond formation through rejection of the aa-tRNA. Steric clash interference is a mechanism of inhibition used by many protein synthesis inhibitors that bind to the functional sites of the mature ribosome (Garreau de Kö nst et al, 2017;McClary et al, 2017;Wilson, 2014).…”

Tetracyclines Modify Translation by Targeting Key Human rRNA Substructures

“…Targeting translation on human cytosolic ribosomes is an emerging strategy for therapeutic intervention in human diseases with dysregulated protein synthesis such as cancer (Bhat et al, 2015; McClary et al, 2017; Myasnikov et al, 2016), with the eukaryotic translation inhibitor homoharringtonine (omacetaxine) recently entering the clinic for treatment of chronic myelogenous leukemia that is refractory to tyrosine kinase inhibition therapy (Gandhi et al, 2014). This work adds tetracyclines to the growing class of small molecules with therapeutic potential in targeting the human ribosomal translational machinery.…”

Tetracyclines Modify Translation By Targeting Key Human rRNA Substructures

“…Targeting translation on human cytosolic ribosomes is an emerging strategy for therapeutic intervention in human diseases with dysregulated protein synthesis such as cancer (Bhat et al, 2015;McClary et al, 2017;Myasnikov et al, 2016) with the eukaryotic translation inhibitor homoharringtonine (omacetaxine) recently entering the clinic for treatment of chronic myelogenous leukemia that is refractory to tyrosine kinase inhibition therapy (Gandhi et al, 2014). This work adds tetracyclines to the growing class of small molecules with therapeutic potential in targeting the human ribosomal translational machinery.…”