Blocking Effect and Crystal Structure of Natrin Toxin, a Cysteine-Rich Secretory Protein from Naja atra Venom that Targets the BKCa Channel †,‡

Cysteine-rich secretory proteins (CRISPs) are widespread in snake venoms. Some members of these CRISPs recently have been found to block L-type Ca2+ channels or cyclic nucleotide-gated ion (CNG) channels. Here, natrin purified from Naja atra venom, a member of the CRISP family, can induce a further contractile response in the endothelium-denuded thoracic aorta of mouse which has been contracted by a high-K+ solution. Further experiments show it can block the high-conductance calcium-activated potassium (BKCa) channel in a concentration-dependent manner with an IC50 of 34.4 nM and a Hill coefficient of 1.02, which suggests that only a single natrin molecule is required to bind an ion channel to block BKCa current. The crystal structure of natrin displaying two domains in tandem shows its cysteine-rich domain (CRD) has relatively independent flexibility, especially for the C-terminal long loop (loop I) of CRD to participate in the interface of two domains. On the basis of previous studies of CNG channel and...