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Structural basis for tetrodotoxin-resistant sodium channel binding by mu-conotoxin SmIIIAStructural basis for tetrodotoxin-resistant sodium channel binding by mu-conotoxin SmIIIA
Structural highlights
FunctionCM3A_CONSE Mu-conotoxins block voltage-gated sodium channels (Nav). This toxin blocks rNav1.5/SCN5A (IC(50) is 1.3 uM), rNav1.6/SCN8A (IC(50) is 160 nM), rNav1.7/SCN9A (IC(50) is 1.3 uM), rNav1.1/SCN1A (K(d) is 3.8 nM), rNav1.2/SCN2A (K(d) is 1.3 nM), rNav1.4/SCN4A (K(d) is 0.22 nM), rNav1.6/SCN8A (K(d) is 69 nM), and rNav1.7/SCN9A (K(d) is 260 nM). This toxin is very potent but weakly discriminating among sodium channels. The block of these channels is modified when beta-subunits are coexpressed with alpha subunits. Hence, blocks of channels containing beta-1 and beta-3 subunits are more potent (compared to channels without beta subunits), whereas blocks of channels containing beta-2 and beta-4 subunits are less potent (compared to channels without beta subunits).[1] [2] [3] [4] Publication Abstract from PubMedSmIIIA 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. 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[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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