Journal
NUCLEIC ACIDS RESEARCH
Volume 47, Issue 6, Pages 3223-3232Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkz053
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Funding
- French National Research Agency [ANR-15-CE11-0021-01]
- La Fondation pour la Recherche Medicale [DBF20160635745]
- European Research Council [294312]
- Russian Government Program of Competitive Growth of Kazan Federal University
- National Institute of Health [GM079238, 1R01GM108889-01, GM129264]
- Swedish Research Council [2017-06313]
- National Science Foundation [CHE-1800431]
- Agence Nationale de la Recherche (ANR) [ANR-15-CE11-0021] Funding Source: Agence Nationale de la Recherche (ANR)
- Swedish Research Council [2017-06313] Funding Source: Swedish Research Council
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Natural products that target the eukaryotic ribosome are promising therapeutics to treat a variety of cancers. It is therefore essential to determine their molecular mechanism of action to fully understand their mode of interaction with the target and to inform the development of new synthetic compounds with improved potency and reduced cytotoxicity. Toward this goal, we have previously established a short synthesis pathway that grants access to multiple congeners of the lissoclimide family. Here we present the X-ray co-crystal structure at 3.1 angstrom resolution of C45, a potent congener with two A-ring chlorine-bearing stereogenic centers with unnatural' configurations, with the yeast 80S ribosome, intermolecular interaction energies of the C45/ribosome complex, and single-molecule FRET data quantifying the impact of C45 on both human and yeast ribosomes. Together, these data provide new insights into the role of unusual non-covalent halogen bonding interactions involved in the binding of this synthetic compound to the 80S ribosome.
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