title: Ternatin and improved synthetic variants kill cancer cells by targeting the elongation factor-1A ternary complex.
abstract: Cyclic peptide natural products have evolved to exploit diverse protein targets, many of which control essential cellular processes. Inspired by a series of cyclic peptides with partially elucidated structures, we designed synthetic variants of ternatin, a cytotoxic and anti-adipogenic natural product whose molecular mode of action was unknown. The new ternatin variants are cytotoxic toward cancer cells, with up to 500-fold greater potency than ternatin itself. Using a ternatin photo-affinity probe, we identify the translation elongation factor-1A ternary complex (eEF1A·GTP·aminoacyl-tRNA) as a specific target and demonstrate competitive binding by the unrelated natural products, didemnin and cytotrienin. Mutations in domain III of eEF1A prevent ternatin binding and confer resistance to its cytotoxic effects, implicating the adjacent hydrophobic surface as a functional hot spot for eEF1A modulation. We conclude that the eukaryotic elongation factor-1A and its ternary complex with GTP and aminoacyl-tRNA are common targets for the evolution of cytotoxic natural products.
authors.affiliation: Chemistry and Chemical Biology Graduate Program, University of California, San Francisco, San Francisco, United States.
authors.forename: Jordan D
authors.identifier: http://orcid.org/0000-0001-7625-7505
authors.initials: JD
authors.lastname: Carelli
authors.affiliation: Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Sethofer
authors.affiliation: Chemistry and Chemical Biology Graduate Program, University of California, San Francisco, San Francisco, United States.
authors.forename: Geoffrey A
authors.initials: GA
authors.lastname: Smith
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, United States.
authors.forename: Howard R
authors.initials: HR
authors.lastname: Miller
authors.affiliation: Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States.
authors.forename: Jillian L
authors.initials: JL
authors.lastname: Simard
authors.affiliation: Department of Biochemistry, School of Medicine, Case Western Reserve University, Cleveland, United States.
authors.forename: William C
authors.initials: WC
authors.lastname: Merrick
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, United States.
authors.forename: Rishi K
authors.initials: RK
authors.lastname: Jain
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, United States.
authors.forename: Nathan T
authors.initials: NT
authors.lastname: Ross
authors.affiliation: Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States.
authors.forename: Jack
authors.initials: J
authors.lastname: Taunton
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D016923:Cell Death; D045744:Cell Line, Tumor; D004351:Drug Resistance; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D050505:Mutant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D009154:Mutation; D020648:Peptide Elongation Factor 1 / Q000037:antagonists & inhibitors* / Q000235:genetics; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000494:pharmacology*; D011485:Protein Binding; D012343:RNA, Transfer / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D050505:Mutant Proteins; D020648:Peptide Elongation Factor 1; D010456:Peptides, Cyclic; C085773:ternatin heptapeptide; D006160:Guanosine Triphosphate; D012343:RNA, Transfer
keywords: biochemistry; cancer; cell biology; cyclic peptide; elongation factor-1A; human; natural product; protein synthesis; target identification