8.C.10. The Sec61-binding Cytotoxin, Ipomoeassin F (Ipomoeassin) Family
Ipomoeassin F is a potent natural cytotoxin that inhibits growth of many tumor cell lines with single-digit nanomolar potency. Zong et al. 2019 used chemical proteomics to identify Sec61α (protein transport protein Sec61 subunit alpha isoform 1), the pore-forming subunit of the Sec61 protein translocon, as a direct binding partner of ipomoeassin F in living cells. The interaction is specific and strong enough to survive lysis conditions, enabling a biotin analogue of ipomoeassin F to pull down Sec61α from live cells, yet it is also reversible. Sec61α forms the central subunit of the ER protein translocation complex, and the binding of ipomoeassin F results in selective inhibition of protein translocation in vitro and in vivo. Ipomoeassin F thus represents a plant-derived, carbohydrate-based member of a novel structural class (Zong et al. 2019).