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End-to-end conformational communication through a synthetic purinergic receptor by ligand-induced helicity switching

Nature Chemistry volume 5, pages 853–860 (2013)Cite this article

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Abstract

The long-range communication of information, exemplified by signal transduction through membrane-bound receptors, is a central biochemical function. Reversible binding of a messenger ligand induces a local conformational change that is relayed through the receptor, inducing a chemical effect typically several nanometres from the binding site. We report a synthetic receptor mimic that transmits structural information from a boron-based ligand binding site to a spectroscopic reporter located more than 2 nm away. Reversible binding of a diol ligand to the N-terminal binding site induces a screw-sense preference in a helical oligo(aminoisobutyric acid) foldamer, which is relayed to a reporter group at the remote C-terminus, communicating information about the structure and stereochemistry of the ligand. The reversible nature of boronate esterification was exploited to switch the receptor sequentially between left- and right-handed helices, while the exquisite conformational sensitivity of the helical relay allowed the reporter to differentiate even between purine and pyrimidine nucleosides as ligands.

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Figure 1: Remote detection of ligand binding to a synthetic receptor by NMR spectroscopy.
Figure 2: Synthesis of boronate-capped receptors used in this study.
Figure 3: Probing ligand-induced conformational control by NMR spectroscopy.
Figure 4: Dynamic switching of screw-sense preference.
Figure 5: Screw-sense control using ribonucleosides as ligands.

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Acknowledgements

This work was funded by the Biotechnology and Biological Sciences Research Council through a Research Grant (I007962) and a Doctoral Training Grant studentship. The authors thank T. Wallace for donating samples of 6c, 6e and 6f. The authors acknowledge the Engineering and Physical Sciences Research Council National Mass Spectrometry Centre for performing high-resolution mass spectrometry measurements.

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Authors and Affiliations

  1. School of Chemistry, University of Manchester, Oxford Road, Manchester, M13 9PL, UK

    Robert A. Brown, Vincent Diemer, Simon J. Webb & Jonathan Clayden

  2. Manchester Institute of Biotechnology, University of Manchester, 131 Princess Street, Manchester, M1 7DN, UK

    Robert A. Brown, Vincent Diemer & Simon J. Webb

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  1. Robert A. Brown
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Contributions

R.A.B., S.J.W. and J.C. conceived and designed the project. R.A.B. and V.D. designed and executed the synthesis of the receptors. R.A.B. performed the analytical studies. R.A.B., S.J.W. and J.C. wrote the paper.

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Correspondence to Simon J. Webb or Jonathan Clayden.

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Brown, R., Diemer, V., Webb, S. et al. End-to-end conformational communication through a synthetic purinergic receptor by ligand-induced helicity switching. Nature Chem 5, 853–860 (2013). https://doi.org/10.1038/nchem.1747

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