1q2j

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Structural basis for tetrodotoxin-resistant sodium channel binding by mu-conotoxin SmIIIA

Overview

SmIIIA is a new micro-conotoxin isolated recently from Conus, stercusmuscarum. Although it shares several biochemical characteristics, with other micro-conotoxins (the arrangement of cysteine residues and a, conserved arginine believed to interact with residues near the channel, pore), it has several distinctive features, including the absence of, hydroxyproline, and is the first specific antagonist of, tetrodotoxin-resistant voltage-gated sodium channels to be characterized., It therefore represents a potentially useful tool to investigate the, functional roles of these channels. We have determined the, three-dimensional structure of SmIIIA in aqueous solution. Consistent with, the absence of hydroxyprolines, SmIIIA adopts a single conformation with, all peptide bonds in the trans configuration. The spatial orientations of, several conserved Arg and Lys side chains, including Arg14 (using a, consensus numbering system), which plays a key role in sodium channel, binding, are similar to those in other micro-conotoxins but the N-terminal, regions differ, reflecting the trans conformation for the peptide bond, preceding residue 8 in SmIIIA, as opposed to the cis conformation in, micro-conotoxins GIIIA and GIIIB. Comparison of the surfaces of SmIIIA, with other micro-conotoxins suggests that the affinity of SmIIIA for, TTX-resistant channels is influenced by the Trp15 side chain, which is, unique to SmIIIA. Arg17, which replaces Lys in the other micro-conotoxins, may also be important. Consistent with these inferences from the, structure, assays of two chimeras of SmIIIA and PIIIA in which their N-, and C-terminal halves were recombined, indicated that residues in the, C-terminal half of SmIIIA confer affinity for tetrodotoxin-resistant, sodium channels in the cell bodies of frog sympathetic neurons. SmIIIA and, the chimera possessing the C-terminal half of SmIIIA also inhibit, tetrodotoxin-resistant sodium channels in the postganglionic axons of, sympathetic neurons, as indicated by their inhibition of C-neuron compound, action potentials that persist in the presence of tetrodotoxin.

About this Structure

1Q2J is a Protein complex structure of sequences from [1]. Full crystallographic information is available from OCA.

Reference

Structural basis for tetrodotoxin-resistant sodium channel binding by mu-conotoxin SmIIIA., Keizer DW, West PJ, Lee EF, Yoshikami D, Olivera BM, Bulaj G, Norton RS, J Biol Chem. 2003 Nov 21;278(47):46805-13. Epub 2003 Sep 10. PMID:12970353

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