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Ligand-modulated conformational switching in a fully synthetic membrane-bound receptor

Abstract

Signal transduction through G-protein-coupled receptors (GPCRs) involves binding to signalling molecules at the cell surface, which leads to global changes in molecular conformation that are communicated through the membrane. Artificial mechanisms for communication involving ligand binding and global conformational switching have been demonstrated so far only in the solution phase. Here, we report a membrane-bound synthetic receptor that responds to binding of a ligand by undergoing a conformational change that is propagated over several nanometres, deep into the phospholipid bilayer. Our design uses a helical foldamer core, with structural features borrowed from a class of membrane-active fungal antibiotics, ligated to a water-compatible, metal-centred binding site and a conformationally responsive fluorophore. Using the fluorophore as a remote reporter of conformational change, we find that binding of specific carboxylate ligands to a Cu(II) cofactor at the binding site perturbs the foldamer's global conformation, mimicking the conformational response of a GPCR to ligand binding.

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Figure 1: Design and function of a synthetic GPCR mimic.
Figure 2: Ligand-induced conformational responses in solution.
Figure 3: Incorporation of the receptor mimic into the membrane of artificial vesicles.
Figure 4: Ligand-induced conformational responses in the membrane phase.

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Acknowledgements

This work was supported by the European Research Council (advanced grant ROCOCO) and the EPRSC (grants EP/N009134/1 and EP/K039547).

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Contributions

S.J.W. and J.C. conceived the project and wrote the paper. F.G.A.L., B.A.F.L.B., S.J.W. and J.C. devised the experiments and analysed the data. F.G.A.L. and B.A.F.L.B. carried out the experiments.

Corresponding authors

Correspondence to Simon J. Webb or Jonathan Clayden.

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The authors declare no competing financial interests.

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Lister, F., Le Bailly, B., Webb, S. et al. Ligand-modulated conformational switching in a fully synthetic membrane-bound receptor. Nature Chem 9, 420–425 (2017). https://doi.org/10.1038/nchem.2736

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