Structural plasticity and dynamic selectivity of acid-sensing ion channel - toxin complexes

Acid-sensing ion channels (ASICs), initially thought to gate solely via proton binding, have been shown to activate through pH-independent mechanisms, revealing diverse roles in the nervous system. To stabilize activated states, we determined crystal structures of ASIC1a bound to spider toxin PcTx1 and snake toxin MitTx. PcTx1 binds near the acidic pocket, while MitTx wedges between subunits, inducing distinct conformational changes. Structural comparisons highlight conserved scaffolds and dynamic regions that mediate gating and ion selectivity. These findings elucidate toxin-binding mechanisms and channel activation, providing a foundation for therapeutic targeting of ASICs.