title: The antibiotic kasugamycin mimics mRNA nucleotides to destabilize tRNA binding and inhibit canonical translation initiation.
abstract: Kasugamycin (Ksg) specifically inhibits translation initiation of canonical but not of leaderless messenger RNAs. Ksg inhibition is thought to occur by direct competition with initiator transfer RNA. The 3.35-A structure of Ksg bound to the 30S ribosomal subunit presented here provides a structural description of two Ksg-binding sites as well as a basis for understanding Ksg resistance. Notably, neither binding position overlaps with P-site tRNA; instead, Ksg mimics codon nucleotides at the P and E sites by binding within the path of the mRNA. Coupled with biochemical experiments, our results suggest that Ksg indirectly inhibits P-site tRNA binding through perturbation of the mRNA-tRNA codon-anticodon interaction during 30S canonical initiation. In contrast, for 70S-type initiation on leaderless mRNA, the overlap between mRNA and Ksg is reduced and the binding of tRNA is further stabilized by the presence of the 50S subunit, minimizing Ksg efficacy.
authors.affiliation: Max-Planck Institute for Molecular Genetics, D-14195 Berlin, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Schluenzen
authors.forename: Chie
authors.initials: C
authors.lastname: Takemoto
authors.forename: Daniel N
authors.initials: DN
authors.lastname: Wilson
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kaminishi
authors.forename: Joerg M
authors.initials: JM
authors.lastname: Harms
authors.forename: Kyoko
authors.initials: K
authors.lastname: Hanawa-Suetsugu
authors.forename: Witold
authors.initials: W
authors.lastname: Szaflarski
authors.forename: Masahito
authors.initials: M
authors.lastname: Kawazoe
authors.forename: Mikako
authors.initials: M
authors.lastname: Shirouzu
authors.forename: Mikako
authors.initials: M
authors.lastname: Shirouzo
authors.forename: Knud H
authors.initials: KH
authors.lastname: Nierhaus
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Yokoyama
authors.forename: Paola
authors.initials: P
authors.lastname: Fucini
mesh_terms: D000617:Aminoglycosides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000737:chemistry; D001665:Binding Sites; D003062:Codon; D004926:Escherichia coli / Q000737:chemistry*; D008958:Models, Molecular; D009711:Nucleotides / Q000737:chemistry; D010442:Peptide Chain Initiation, Translational; D017434:Protein Structure, Tertiary; D012329:RNA, Bacterial / Q000737:chemistry*; D012333:RNA, Messenger / Q000737:chemistry*; D012343:RNA, Transfer / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D003062:Codon; D009711:Nucleotides; D012329:RNA, Bacterial; D012333:RNA, Messenger; D012343:RNA, Transfer; C100305:kasugamycin