| Research Abstract |
ω-Grammotoxin SlA (GrTx) is a 36 amino acid residue protein toxin from spider venom that inhibits P/Q and N type voltage-gated Ca^<2+> channels by modifying voltage-dependent gating. We determined the three-dimensional structure of GrTx using NMR spectroscopy. The toxin adopts an 'inhibitor cystine knot' motif composed of two β-strands (Leu19 - Cys21 and Cys30 - Trp32) and a β-bulge (Trp6, Gry7 - Cys30) with a +2x, 1 topology, which are connected by four chain reversals. Although GrTx was originally identified as an inhibitor of voltage-gated Ca^<2+> channel, it also binds to K^+ channels with lower affinity. A similar cross-reaction was observed for HaTx, which binds to the voltage-sensing domains of K^+ and Ca^<2+> channels with different affinities. A detailed comparison of the GrTx and HaTx structures identifies a well-conserved face containing a large hydrophobic patch surrounded by positively charged residues. The slight differences in the surface shape, which result from the orientation of the surface aromatic residues and/or the distribution of the charged residues, may explain differences in the binding affinity of these gating modifiers with different voltage-gated ion channels.
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