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Can Structures Lead to Better Drugs? Lessons from Ribosome Research

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From Molecules to Medicines

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Abstract

Ribosome research has undergone astonishing progress in recent years. Crystal structures have shed light on the functional properties of the translation machinery and revealed how the ribosome's striking architecture is ingeniously designed as the framework for its unique capabilities: precise decoding, substrate mediated peptide-bond formation and efficient poly-merase activity. New findings include the two concerted elements of tRNA translocation: sideways shift and a ribosomal-navigated rotatory motion; the dynamics of the nascent chain exit tunnel and the shelter formed by the ribosome-bound trigger-factor, which acts as a chaperone to prevent nascent chain aggregation and misfolding.

These linkage between these findings and crystal structures of ribosomes with over two dozen antibiotics targeting the ribosome, most of which of a high therapeutical relevance, illuminated various modes of binding and action of these antibiotics; deciphered mechanisms leading to resistance; identified the principles allowing for the discrimination between pathogens and eukaryotes despite the high ribosome conservation; enlightened the basis for antibiotics synergism, namely the conversion of two weakly acting compounds to a powerful antibiotic agent; indicated correlations between antibiotics susceptibility and fitness cost and revealed an novel induced-fit mechanism exploiting ribosomal inherent flexibility for reshape the antibiotic binding pocket by remote interactions.

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Authors and Affiliations

  1. Department of Structural Biology, Weizmann Institute, Rehovot, Israel

    Ada Yonath

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  1. Ada Yonath
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Editors and Affiliations

  1. Department of Structural Biology, Weizmann Institute of Science, Rehovot, Israel

    Joel L. Sussman

  2. Department of Chemical Sciences, University of Padova, Italy

    Paola Spadon

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Yonath, A. (2009). Can Structures Lead to Better Drugs? Lessons from Ribosome Research. In: Sussman, J.L., Spadon, P. (eds) From Molecules to Medicines. NATO Science for Peace and Security Series A: Chemistry and Biology. Springer, Dordrecht. https://doi.org/10.1007/978-90-481-2339-1_15

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