Centre for Advanced Imaging, The University of Queensland, St Lucia, Australia
Voltage-gated ion channels comprise one of the largest superfamilies of signal transduction proteins and are also among the most common drug targets. Disulfide rich venom peptides are natural and often non-specific ligands of voltage-gated ion channels. A number of these peptides act by binding to specific voltage sensor domains (VSDs) and trapping the channel in either an ion-conducting or non ion-conducting state of the gating cycle. Although there is great scope for utilising the mode of action of gating modifier peptides for drug discovery, little is known about the structural details of the peptide-channel interactions. There have been a number of studies that have provided clues to how these peptides may bind to the VSDs, yet there is still much controversy regarding the structure of the peptide-VSD complex. Here we used NMR spectrosocpy to identify the binding surfaces of the isolated VSD of a voltage-gated potassium channel (KvAP) and its venom peptide antagonist, VSTx1 at atomic resolution. This data allowed us to propose a novel 3D structural model of the complex, which contradicts current paradigms but is consistent with nearly a decades worth of functional data on the binding of this class of peptides to several human voltage-gated ion channels. Our findings provide a structural framework that will enable us to engineer selective ion channel modulators with significant potential for treating a wide range of diseases including chronic pain, epilepsy and autoimmune disorders.
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