Crystal Structure of a Bioactive Pactamycin Analog Bound to the 30S Ribosomal Subunit

Biosynthetically and chemically derived analogs of the antibiotic pactamycin and de-6-methylsalicylyl (MSA)-pactamycin have attracted recent interest as potential antiprotozoal and antitumor drugs. Here, we report a 3.1-Å crystal structure of de-6-MSA-pactamycin bound to its target site on the Therm...

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Bibliographic Details
Published in:Journal of molecular biology 2013-10, Vol.425 (20), p.3907-3910
Main Authors: Tourigny, David S., Fernández, Israel S., Kelley, Ann C., Vakiti, Ramkrishna Reddy, Chattopadhyay, Amit Kumar, Dorich, Stéphane, Hanessian, Stephen, Ramakrishnan, V.
Format: Article
Language:English
Subjects:
antibiotic
antibiotics
Antibiotics, Antineoplastic - chemistry
Antibiotics, Antineoplastic - metabolism
antineoplastic agents
binding sites
Brevia
crystal structure
Crystallography, X-Ray
E-site
Models, Molecular
Molecular Conformation
mRNA
nucleic acids
Pactamycin - analogs & derivatives
Pactamycin - chemistry
Pactamycin - metabolism
Protein Binding
Ribosome Subunits, Small, Bacterial - chemistry
Ribosome Subunits, Small, Bacterial - metabolism
ribosomes
RNA, Ribosomal, 16S - chemistry
RNA, Ribosomal, 16S - metabolism
Thermus thermophilus
Thermus thermophilus - metabolism
translation
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Summary:Biosynthetically and chemically derived analogs of the antibiotic pactamycin and de-6-methylsalicylyl (MSA)-pactamycin have attracted recent interest as potential antiprotozoal and antitumor drugs. Here, we report a 3.1-Å crystal structure of de-6-MSA-pactamycin bound to its target site on the Thermus thermophilus 30S ribosomal subunit. Although de-6-MSA-pactamycin lacks the MSA moiety, it shares the same binding site as pactamycin and induces a displacement of nucleic acid template bound at the E-site of the 30S. The structure highlights unique interactions between this pactamycin analog and the ribosome, which paves the way for therapeutic development of related compounds. [Display omitted] •The potential antitumor drug de-6-MSA-pactamycin retains equivalent biological activity to pactamycin.•We present a 3.1-Å crystal structure of the 30S ribosomal subunit bound to de-6-MSA-pactamycin that describes the interactions between pactamycin analogs and the ribosome.•The structure reveals de-6-MSA-pactamycin functions by disrupting base pairing at the E-site, which can be exploited for therapeutic purposes.
ISSN:0022-2836
1089-8638
DOI:10.1016/j.jmb.2013.05.004