Abstract

Translation, the mRNA-templated synthesis of peptides by the ribosome, can be manipulated to incorporate variants of the 20 cognate amino acids. Such approaches for expanding the range of chemical entities that can be produced by the ribosome may accelerate the discovery of molecules that can perform functions for which poorly folded, short peptidic sequences are ill suited. Here, we show that the ribosome tolerates some artificial helical aromatic oligomers, so-called foldamers. Using a flexible tRNA-acylation ribozyme—flexizyme—foldamers were attached to tRNA, and the resulting acylated tRNAs were delivered to the ribosome to initiate the synthesis of non-cyclic and cyclic foldamer–peptide hybrid molecules. Passing through the ribosome exit tunnel requires the foldamers to unfold. Yet foldamers encode sufficient folding information to influence the peptide structure once translation is completed. We also show that in cyclic hybrids, the foldamer portion can fold into a helix and force the peptide segment to adopt a constrained and stretched conformation.

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Change history

  • 31 May 2018

    In the version of this Article originally published, in Fig.1f there was an erroneous ‘Gly–Gly’ label placed above the foldamer–peptide structure. Furthermore, in Fig. 2a, the expected target structures from substrates 9 and 10 were inadvertently swapped. These errors have been corrected in the online versions.

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Acknowledgements

This work was mainly supported by a joint ANR-JST grant (ANR-14-JTIC-2014-003 and JST-SICORP, to H.S. and I.H.), and partly supported by the European Research Council under the European Union’s Seventh Framework Programme (ERC-2012-AdG-320892 to I.H.), a Japan Society for the Promotion of Science post-doctoral fellowship (P13766, to J.M.R.) and the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2016R1A6A3A03006364, to S.K). This work benefited from the facilities and expertise of the Biophysical and Structural Chemistry platform at IECB, CNRS UMS3033, INSERM US001, Bordeaux University, France.

Author information

Author notes

    • Ivan Huc

    Present address: Department of Pharmacy, Ludwig-Maximilians-Universität, München, Germany

  1. These authors contributed equally: Joseph M. Rogers, Sunbum Kwon.

Affiliations

  1. Department of Chemistry, Graduate School of Science, The University of Tokyo, Tokyo, Japan

    • Joseph M. Rogers
    •  & Hiroaki Suga
  2. CBMN Laboratory, Univ. Bordeaux, CNRS, IPB, Institut Européen de Chimie et Biologie, Pessac, France

    • Sunbum Kwon
    • , Simon J. Dawson
    • , Pradeep K. Mandal
    •  & Ivan Huc

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Contributions

S.K. and J.M.R. contributed equally to this work. S.K. and S.J.D. synthesized new compounds. S.K. carried out solution conformational studies. J.M.R. performed in vitro aminoacylation and translation experiments. P.K.M. carried out crystallographic studies. All authors contributed to designing the research, to discussing the results and to writing the manuscript.

Competing interests

The authors declare no competing interests.

Corresponding authors

Correspondence to Hiroaki Suga or Ivan Huc.

Supplementary information

  1. Supplementary Information

    Supplementary Figs. 1–35, Supplementary Methods and data

  2. Supplementary Movie 1

    Crystal structure of macrocyclic foldamer-peptide hybrid 17

  3. Crystallographic data

    Crystallographic data for compound 17, CCDC reference 1554263

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DOI

https://doi.org/10.1038/s41557-018-0007-x