Ligand-modulated conformational switching in a fully synthetic membrane-bound receptor
Ligand-modulated conformational switching in a fully synthetic membrane-bound receptor
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DOI：
10.1038/nchem.2736
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发表时间：
2017-05-01
期刊：
影响因子：
21.8
通讯作者：
Clayden, Jonathan
中科院分区：
文献类型：
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作者：
Lister, Francis G. A.;Le Bailly, Bryden A. F.;Clayden, Jonathan
通过G蛋白偶联受体（GPCR）的信号转导涉及与细胞表面的信号分子结合，这导致通过膜传递的分子构象的全局变化。涉及配体结合和全局构象转换的人工通信机制迄今为止仅在溶液相中得到证实。在这里，我们报告了一种膜结合的合成受体，通过经历构象变化，传播超过几个纳米，深入到磷脂双分子层的配体的结合。我们的设计使用螺旋折叠体核心，其结构特征借用自一类膜活性真菌抗生素，连接到水相容的、以金属为中心的结合位点和构象响应荧光团。使用的荧光团作为一个远程报告员的构象变化，我们发现，特定的羧酸配体的铜（II）辅因子在结合位点的结合扰动的折叠体的全局构象，模仿的构象响应的GPCR配体结合。
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.