Saxiphilin is a broad-spectrum toxin sponge for C13-modified saxitoxins

Saxitoxin (STX) and its congeners (paralytic shellfish toxins, PSTs) are among the most potent small-molecule toxins. PSTs are produced by harmful algal blooms and derive toxicity by disrupting voltage-gated sodium channel (Na_V) bioelectrical signaling. Understanding how PST structural variation affects target binding is crucial to develop means to counteract PSTs and exploit these natural products as drug development leads. Frog and toad saxiphilins (Sxphs) are soluble, high-affinity STX toxin sponge proteins that offer a powerful platform to define PST-protein interactions. Here, we show that American bullfrog (Rana catesbeiana) RcSxph and High Himalaya frog (Nanorana parkeri) NpSxph bind a broad set of C13-modified STX congeners. High-resolution X-ray crystal structures of toxin complexes with RcSxph, RcSxph mutants, and NpSxph unveil two C13-aryl congener binding modes, termed 'compact' and 'open', that depend on the RcSxph Tyr558 local environment. These results highlight a remarkable adaptability of Sxphs for accommodating chemically diverse STX analogs and reveal unexpected toxin conformational plasticity. These findings have implications for understanding PST interactions with biological targets and informing design of STX-based probes and Na_V modulators.