A scorpion toxin affecting sodium channels shows double cis-trans isomerism.

Scorpion α-toxins (α-NaTx) inhibiting the inactivation of voltage-gated sodium channels (Na v ) are a well-studied family of small proteins. We previously showed that the structure of α-NaTx specificity module responsible for selective Na v binding is governed by an interplay between the nest and niche protein motifs. Here, we report the solution structure of the toxin Lqq4 from the venom of the scorpion Leiurus quinquestriatus. Unexpectedly, we find that this toxin presents an ensemble of long-lived structurally distinct states. We unequivocally assign these states to the alternative configurations (cis-trans isomers) of two peptide bonds: V56-P57 and C17-G18; neithe of the cis isomers has been described in α-NaTx so far. We argue that the native conformational space of α-NaTx is wider than assumed previously.