title: Amicoumacin a inhibits translation by stabilizing mRNA interaction with the ribosome.
abstract: We demonstrate that the antibiotic amicoumacin A (AMI) is a potent inhibitor of protein synthesis. Resistance mutations in helix 24 of the 16S rRNA mapped the AMI binding site to the small ribosomal subunit. The crystal structure of bacterial ribosome in complex with AMI solved at 2.4 Å resolution revealed that the antibiotic makes contacts with universally conserved nucleotides of 16S rRNA in the E site and the mRNA backbone. Simultaneous interactions of AMI with 16S rRNA and mRNA and the in vivo experimental evidence suggest that it may inhibit the progression of the ribosome along mRNA. Consistent with this proposal, binding of AMI interferes with translocation in vitro. The inhibitory action of AMI can be partly compensated by mutations in the translation elongation factor G.
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA; Howard Hughes Medical Institute, Yale University, New Haven, CT 06520, USA.
authors.forename: Yury S
authors.initials: YS
authors.lastname: Polikanov
authors.affiliation: Lomonosov Moscow State University, Department of Chemistry and A.N. Belozersky Institute of Physico-Chemical Biology, 119992 Moscow, Russia.
authors.forename: Ilya A
authors.initials: IA
authors.lastname: Osterman
authors.affiliation: Center for Pharmaceutical Biotechnology, University of Illinois at Chicago, Chicago, IL 60607, USA.
authors.forename: Teresa
authors.initials: T
authors.lastname: Szal
authors.affiliation: Lomonosov Moscow State University, Department of Chemistry and A.N. Belozersky Institute of Physico-Chemical Biology, 119992 Moscow, Russia.
authors.forename: Vadim N
authors.initials: VN
authors.lastname: Tashlitsky
authors.affiliation: Lomonosov Moscow State University, Department of Chemistry and A.N. Belozersky Institute of Physico-Chemical Biology, 119992 Moscow, Russia.
authors.forename: Marina V
authors.initials: MV
authors.lastname: Serebryakova
authors.affiliation: Lomonosov Moscow State University, Department of Chemistry and A.N. Belozersky Institute of Physico-Chemical Biology, 119992 Moscow, Russia.
authors.forename: Pavel
authors.initials: P
authors.lastname: Kusochek
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA.
authors.forename: David
authors.initials: D
authors.lastname: Bulkley
authors.affiliation: G.F. Gause Institute of New Antibiotics, Russian Academy of Medical Sciences, 119867 Moscow, Russia.
authors.forename: Irina A
authors.initials: IA
authors.lastname: Malanicheva
authors.affiliation: G.F. Gause Institute of New Antibiotics, Russian Academy of Medical Sciences, 119867 Moscow, Russia.
authors.forename: Tatyana A
authors.initials: TA
authors.lastname: Efimenko
authors.affiliation: G.F. Gause Institute of New Antibiotics, Russian Academy of Medical Sciences, 119867 Moscow, Russia.
authors.forename: Olga V
authors.initials: OV
authors.lastname: Efremenkova
authors.affiliation: B.P. Konstantinov Petersburg Nuclear Physics Institute, 188300 Gatchina, Russia; Saint Petersburg State Polytechnical University, Polytechnicheskaya 29, 195251 Saint Petersburg, Russia.
authors.forename: Andrey L
authors.initials: AL
authors.lastname: Konevega
authors.affiliation: Hearts Consulting Group, San Diego, CA 92127, USA.
authors.forename: Karen J
authors.initials: KJ
authors.lastname: Shaw
authors.affiliation: Lomonosov Moscow State University, Department of Chemistry and A.N. Belozersky Institute of Physico-Chemical Biology, 119992 Moscow, Russia.
authors.forename: Alexey A
authors.initials: AA
authors.lastname: Bogdanov
authors.affiliation: Max Planck Institute for Biophysical Chemistry, 37077 Gottingen, Germany.
authors.forename: Marina V
authors.initials: MV
authors.lastname: Rodnina
authors.affiliation: Lomonosov Moscow State University, Department of Chemistry and A.N. Belozersky Institute of Physico-Chemical Biology, 119992 Moscow, Russia.
authors.forename: Olga A
authors.initials: OA
authors.lastname: Dontsova
authors.affiliation: Center for Pharmaceutical Biotechnology, University of Illinois at Chicago, Chicago, IL 60607, USA. Electronic address: shura@uic.edu.
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Mankin
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA; Howard Hughes Medical Institute, Yale University, New Haven, CT 06520, USA. Electronic address: thomas.steitz@yale.edu.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Steitz
authors.affiliation: Lomonosov Moscow State University, Department of Chemistry and A.N. Belozersky Institute of Physico-Chemical Biology, 119992 Moscow, Russia. Electronic address: petya@genebee.msu.ru.
authors.forename: Petr V
authors.initials: PV
authors.lastname: Sergiev
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D001426:Bacterial Proteins / Q000235:genetics; D001483:Base Sequence; D001665:Binding Sites; D003374:Coumarins / Q000737:chemistry* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D024881:Drug Resistance, Bacterial; D004926:Escherichia coli; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D020653:Peptide Elongation Factor G / Q000235:genetics; D014176:Protein Biosynthesis / Q000187:drug effects*; D011500:Protein Synthesis Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism; D054681:Ribosome Subunits, Large, Bacterial / Q000737:chemistry; D054680:Ribosome Subunits, Small, Bacterial / Q000737:chemistry; D013211:Staphylococcus aureus / Q000235:genetics; D016963:Thermus thermophilus
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D003374:Coumarins; D020653:Peptide Elongation Factor G; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; C031379:amicoumacin A