Probing the structural details of ion-channel function using venom peptides
Centre for Advanced Imaging, The University of Queensland, 4072, St Lucia, Queensland, Australia.
Ion channels and their structural relatives comprise one of the largest superfamilies of signal transduction proteins. Unsurprisingly, these ion channels are also among the most common drug targets. Ion channels, however, have proven particularly recalcitrant to traditional drug discovery approaches and our work seeks to address this through improved understanding of the structure and function of these channels.1 Disulfide rich venom peptides are known to include molecules that modulate the activity of ion channels by unique allosteric mechanisms.2 These peptides, provide an excellent opportunity to study the structural details of channel inhibition for drug development. I will present work from our group that overcome difficulties in the production and characterisation of these cysteine stabilised peptides, allowing them to be used for probing channel structure and function.3 Our group is currently also developing methods to stabilise the ligand binding domain of the membrane embedded ion-channels in solution using lipid nanodiscs for high-resolution structural studies by nuclear magnetic resonance (NMR) spectroscopy and high-throughput screening assays, capable of identifying weak allosteric modulators. In combination with existing cell-based assays it is anticipated that this will provide a new approach to identifying drug candidates in a field that has proven challenging for drug development. References: 1. Zhang, A.; Sharma, G.; Undheim, E. A. B.; Jia, X.; Mobli, M., A complicated complex: ion channels, voltage sensing, cell membranes and peptide inhibitors. Neuroscience Letters 2018, In press (accepted 2018-01-11). 2. Mobli, M.; Undheim, E. A. B.; Rash, L. D., Modulation of Ion Channels by Cysteine-Rich Peptides: From Sequence to Structure. In Advances in Pharmacology, Geraghty, D. P.; Rash, L. D., Eds. Academic Press: 2017; Vol. 79, pp 199-223. 3. Miljenovic, T. M.; Jia, X.; Mobli, M., Nonuniform Sampling in Biomolecular NMR. In Modern Magnetic Resonance, Webb, G. A., Ed. Springer International Publishing: Cham, 2018; pp 2035-2054.