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Mol Cell. 2014 Nov 20;56(4):531-40. doi: 10.1016/j.molcel.2014.09.020. Epub 2014 Oct 9.

Amicoumacin a inhibits translation by stabilizing mRNA interaction with the ribosome.

Author information

1
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA; Howard Hughes Medical Institute, Yale University, New Haven, CT 06520, USA.
2
Lomonosov Moscow State University, Department of Chemistry and A.N. Belozersky Institute of Physico-Chemical Biology, 119992 Moscow, Russia.
3
Center for Pharmaceutical Biotechnology, University of Illinois at Chicago, Chicago, IL 60607, USA.
4
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA.
5
G.F. Gause Institute of New Antibiotics, Russian Academy of Medical Sciences, 119867 Moscow, Russia.
6
B.P. Konstantinov Petersburg Nuclear Physics Institute, 188300 Gatchina, Russia; Saint Petersburg State Polytechnical University, Polytechnicheskaya 29, 195251 Saint Petersburg, Russia.
7
Hearts Consulting Group, San Diego, CA 92127, USA.
8
Max Planck Institute for Biophysical Chemistry, 37077 Gottingen, Germany.
9
Center for Pharmaceutical Biotechnology, University of Illinois at Chicago, Chicago, IL 60607, USA. Electronic address: shura@uic.edu.
10
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.
11
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.

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.

PMID:
25306919
PMCID:
PMC4253140
DOI:
10.1016/j.molcel.2014.09.020
[Indexed for MEDLINE]
Free PMC Article

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