Modulation of Ion Channels by Cysteine-Rich Peptides: From Sequence to Structure.

Venom peptides are natural ligands of ion channels and have been used extensively in pharmacological characterization of various ion channels and receptors. In this chapter, we survey all known venom peptide ion-channel modulators. Our survey reveals that the majority of venom peptides characterized to date target voltage-gated sodium or potassium channels. We further find that the majority of these peptides are found in scorpion and spider venoms. We discuss the influence of the pharmacological tools available in biasing discovery and the classical "toxin-to-sequence" approach to venom peptide biodiscovery. The impact of high-throughput sequencing on the existing discovery framework is likely to be significant and we propose here an alternative "sequence-to-toxin" approach to peptide screening, relying more on recently developed high-throughput methods. Methods for production and characterization of disulfide rich toxins in a high-throughput setting are then described, focusing on bacterial protein expression and solution state structural characterization by NMR spectroscopy. Finally, the role of X-ray crystallography and cryo-EM are highlighted by discussing the currently known channel-peptide complexes.