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The structure of ribosome-lankacidin complex reveals ribosomal sites for synergistic antibiotics

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Title: The structure of ribosome-lankacidin complex reveals ribosomal sites for synergistic antibiotics
Author(s): Auerbach, Tamar; Mermershtain, Inbal; Davidovich, Chen; Bashan, Anat; Belousoff, Matthew; Wekselman, Itai; Zimmerman, Ella; Xiong, Liqun; Klepacki, Dorota; Mankin, Alexander; Yonath, Ada
Abstract: Crystallographic analysis revealed that the 17-member polyketide antibiotic lankacidin produced by Streptomyces rochei, binds at the peptidyl transferase center of the ubacterial large ribosomal subunit. Biochemical and functional studies verified this finding and showed interference with peptide bond formation. Chemical probing indicated that the macrolide lankamycin, an additional antibiotic produced by the same species, binds at a neighboring site, at the ribosome exit tunnel. Thus, it appears that lankacidin and lankamycin have been evolutionary optimized to interact with the ribosome simultaneously and that their dual action results in a synergistic inhibition of cell growth. The binding site of lankacidin and lankamycin partially overlap with the binding site of another pair of synergistic antibiotics, the streptogramins composing synercid. Thus, at least two pairs of structurally dissimilar compounds have been selected in the course of evolution to act synergistically by targeting neighboring sites in the ribosome. These results underscore the importance of the corresponding ribosomal sites for development of clinically-relevant synergistic antibiotics and demonstrate the utility of structural analysis for providing new directions for drug discovery.
Issue Date: 2010
Publisher: National Academy of Sciences
Citation Info: David-Eden, H., Mankin, A. S., & Mandel-Gutfreund, Y. 2010. Structural signatures of antibiotic binding sites on the ribosome. Proc Natl Acad Sci U S A. 2010 February 2; 107(5): 1983–1988. doi: 10.1073/pnas.0914100107
Type: Article
Description: © 2010 by National Academy of Sciences. This is a copy of an article published in the Proceedings of the National Academy of Sciences © 2010. doi: 10.1073/pnas.0914100107
URI: http://hdl.handle.net/10027/8302
ISSN: 0305-1048
Sponsor: This work was supported by the US National Institutes of Health grants GM34360 (to AY), and U19 AI56575 (to ASM) and by Kimmelman Center for Macromolecular Assemblies. CD is supported by the Adams Fellowship Program of the Israel Academy of Sciences and Humanities.
Date Available in INDIGO: 2012-04-30
 

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