title: Identification of elongation factor G as the conserved cellular target of argyrin B.
abstract: Argyrins, produced by myxobacteria and actinomycetes, are cyclic octapeptides with antibacterial and antitumor activity. Here, we identify elongation factor G (EF-G) as the cellular target of argyrin B in bacteria, via resistant mutant selection and whole genome sequencing, biophysical binding studies and crystallography. Argyrin B binds a novel allosteric pocket in EF-G, distinct from the known EF-G inhibitor antibiotic fusidic acid, revealing a new mode of protein synthesis inhibition. In eukaryotic cells, argyrin B was found to target mitochondrial elongation factor G1 (EF-G1), the closest homologue of bacterial EF-G. By blocking mitochondrial translation, argyrin B depletes electron transport components and inhibits the growth of yeast and tumor cells. Further supporting direct inhibition of EF-G1, expression of an argyrin B-binding deficient EF-G1 L693Q variant partially rescued argyrin B-sensitivity in tumor cells. In summary, we show that argyrin B is an antibacterial and cytotoxic agent that inhibits the evolutionarily conserved target EF-G, blocking protein synthesis in bacteria and mitochondrial translation in yeast and mammalian cells.
authors.affiliation: Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research, Cambridge, Massachussetts, United States of America.
authors.forename: Beat
authors.initials: B
authors.lastname: Nyfeler
authors.forename: Dominic
authors.initials: D
authors.lastname: Hoepfner
authors.forename: Deborah
authors.initials: D
authors.lastname: Palestrant
authors.forename: Christina A
authors.initials: CA
authors.lastname: Kirby
authors.forename: Lewis
authors.initials: L
authors.lastname: Whitehead
authors.forename: Robert
authors.initials: R
authors.lastname: Yu
authors.forename: Gejing
authors.initials: G
authors.lastname: Deng
authors.forename: Ruth E
authors.initials: RE
authors.lastname: Caughlan
authors.forename: Angela L
authors.initials: AL
authors.lastname: Woods
authors.forename: Adriana K
authors.initials: AK
authors.lastname: Jones
authors.forename: S Whitney
authors.initials: SW
authors.lastname: Barnes
authors.forename: John R
authors.initials: JR
authors.lastname: Walker
authors.forename: Swann
authors.initials: S
authors.lastname: Gaulis
authors.forename: Ervan
authors.initials: E
authors.lastname: Hauy
authors.forename: Saskia M
authors.initials: SM
authors.lastname: Brachmann
authors.forename: Philipp
authors.initials: P
authors.lastname: Krastel
authors.forename: Christian
authors.initials: C
authors.lastname: Studer
authors.forename: Ralph
authors.initials: R
authors.lastname: Riedl
authors.forename: David
authors.initials: D
authors.lastname: Estoppey
authors.forename: Thomas
authors.initials: T
authors.lastname: Aust
authors.forename: N Rao
authors.initials: NR
authors.lastname: Movva
authors.forename: Zuncai
authors.initials: Z
authors.lastname: Wang
authors.forename: Michael
authors.initials: M
authors.lastname: Salcius
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Michaud
authors.forename: Gregory
authors.initials: G
authors.lastname: McAllister
authors.forename: Leon O
authors.initials: LO
authors.lastname: Murphy
authors.forename: John A
authors.initials: JA
authors.lastname: Tallarico
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Wilson
authors.forename: Charles R
authors.initials: CR
authors.lastname: Dean
mesh_terms: D000495:Allosteric Site; D000595:Amino Acid Sequence; D000818:Animals; D019117:Burkholderia / Q000187:drug effects; D045744:Cell Line, Tumor; D017124:Conserved Sequence; D018360:Crystallography, X-Ray; D006801:Humans; D008322:Mammals; D008826:Microbial Sensitivity Tests; D024101:Mitochondrial Proteins / Q000378:metabolism; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D020653:Peptide Elongation Factor G / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D017386:Sequence Homology, Amino Acid
chemical_list: D024101:Mitochondrial Proteins; D050505:Mutant Proteins; D009842:Oligopeptides; D020653:Peptide Elongation Factor G; C467071:argyrin B