Web Release Date: July 7,
Blocking Effect and Crystal Structure of Natrin Toxin, a Cysteine-Rich Secretory
Protein from Naja atra Venom that Targets the BKCa Channel
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Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China, Key Laboratory of Structural Biology, Chinese Academy of Sciences, and MacCHESS, Cornell High Energy Synchrotron Source, Cornell University, Ithaca, New York 14853
Received April 3, 2005
Revised Manuscript Received June 6, 2005
Abstract:
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 L-Ca2+ channel blockers, and the sequence and structural comparison of natrin and stecrisp, the deviation of the vital loop I of CRD is suggested to contribute to different effects of some CRISPs in protein-protein interaction.
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