Investigations into cell signalling by NMR Seminar

Communication between cells relies extensively on integral membrane proteins to recognise the presence of external stimuli including neurotransmitters and hormones and mediate the transfer of information across the plasma membrane to initiate an intracellular response. Due to their favourable location in a number of cell signalling pathways they represent a attractive target for the development of novel pharmaceuticals, with over 60% of currently marketed drugs acting on integral membrane proteins. Despite their clear pharmacology importance, our current understanding of how integral membrane proteins functional at the molecular level is still compromised by the challenges associated with obtaining high-resolution structural information. Over the last 25 years solid-state NMR has emerged as a powerful technique for probing the structure and function of integral membrane proteins within their native lipid bilayer. In this lecture I will describe how solid-state NMR has contributed to the structural characterisation and localisation of drugs within their binding sites on integral membrane proteins focussing on ligand gated and voltage gated ion channels, two key families of protein involved in neuronal signalling. In conjunction with recent progress in X-ray crystallographic analysis of integral membrane proteins, I will highlight how this is providing us with novel insights into the function and regulation of integral membrane proteins, key information for the rational development of drugs against these important pharmaceutical targets.