A catalytic protein-proteomimetic complex: using aromatic oligoamide foldamers as activators of RNase S

Zsofia Hegedus, Claire M. Grison, Jennifer A. Miles, Silvia Rodriguez-Marin, Stuart L. Warriner, Michael E. Webb, Andrew J. Wilson*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)

Abstract

Foldamers are abiotic molecules that mimic the ability of bio-macromolecules to adopt well-defined and organised secondary, tertiary or quaternary structure. Such templates have enabled the generation of defined architectures which present structurally defined surfaces that can achieve molecular recognition of diverse and complex targets. Far less explored is whether this mimicry of nature can extend to more advanced functions of biological macromolecules such as the generation and activation of catalytic function. In this work, we adopt a novel replacement strategy whereby a segment of protein structure (the S-peptide from RNase S) is replaced by a foldamer that mimics an α-helix. The resultant prosthetic replacement forms a non-covalent complex with the S-protein leading to restoration of catalytic function, despite the absence of a key catalytic residue. Thus this functional protein-proteomimetic complex provides proof that significant segments of protein can be replaced with non-natural building blocks that may, in turn, confer advantageous properties.

Original languageEnglish
Pages (from-to)3956-3962
Number of pages7
JournalChemical Science
Volume10
Issue number14
DOIs
Publication statusPublished - 14 Apr 2019

Bibliographical note

Funding Information:
This work was supported by the Leverhulme Trust [RPG-2013-065], the European Research Council [ERC-StG-240324 and ERC-PoC-632207], the EPSRC [EP/N013573/1, EP/KO39292/1], for funding NMR facilities and The Wellcome Trust [097827/ Z/11/A] for funding HPLC facilities. This project has received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No. MSCA-IF-2016-749012. We thank Valeria Azzarito, George Burslem, Kerya Long and Panchami Prabhakaran who previously prepared proteomimetics that were screened in this study. We thank Dr Thomas A Edwards for useful discussions.

Publisher Copyright:
© The Royal Society of Chemistry.

ASJC Scopus subject areas

  • General Chemistry

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