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

Abstract

. Ligandmodulated conformational switching in a fully synthetic membrane-bound receptor. Nature Chemistry, 9(5), [420][421][422][423][424][425] University of Bristol -Explore Bristol Research General rightsThis document is made available in accordance with publisher policies. Please cite only the published version using the reference above. AbstractSignal 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.

Signal transduction in oligoamide foldamers by selective non-covalent binding of chiral phosphates at a urea binding site

“…Incorporation of a urea-based anion recognition site into an amide foldamer allows the foldamer to respond to an environmental signal -a hydrogen-bonded interaction with a chiral anion -by changing its global conformational preference. This simple hydrogen-bonded mechanism of interaction complements the design of related binding sites based on boron, 35 copper, 37 or basic nitrogen 32 centres. Non-covalent interaction mediated by hydrogen bonding leads to solvent-dependent asymmetric induction of screw sense preference to differing extents, according to the pairing of various binding sites with various chiral phosphates.…”

“…32 Other examples similarly made use of specific functionality at a designed binding site (for example incorporating a boron, 35 zinc, 23 or copper 37 based 'cofactor') to enforce selective interactions with the foldamer chain.…”

“…22 We have reported 'dynamic foldamers' 23 based on helical oligomers of 2-aminoisobutyric acid (Aib) [24][25][26][27][28][29][30][31] that undergo switching between alternative conformations in response to a variety of stimuli (pH, 32,33 irradiation with light, 33,34 or addition of ligands) 35 both in solution and in the membrane phase. 36,37 The utilisation of dynamic foldamers as signal transduction devices offers a potential synthetic approach to the construction of biomimetic signalling networks.…”

The Chain of Chirality Transfer as Determinant of Brain Functional Laterality. Breaking the Chirality Silence: Search for New Generation of Biomarkers; Relevance to Neurodegenerative Diseases, Cognitive Psychology, and Nutrition Science

“…These studies reveal that molecular chirality directs whole-cell chirality XXXI [8]. At the cellular level, signal transduction involves the wave of chiral transformations in the protein-phospholipid interactions [204][205][206].…”

Triggered Release from Lipid Bilayer Vesicles by an Artificial Transmembrane Signal Transduction System

“…[3][4][5][6][7][8][9] However, mimicking signal transduction and amplification processes that occur without physical transfer of matter has proved a considerable challenge for synthetic systems. [10][11][12][13][14][15] Recently, we have shown that a new abiotic mechanism -membrane translocation -can be used for signal transduction across lipid bilayers in artificial systems ( Figure 1a). The reversible movement of a synthetic transducer molecule across a bilayer can be controlled by chemical input signals on the outside of the vesicle.…”