1Q2J

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

Summary for 1Q2J

• Entry DOI: 10.2210/pdb1q2j/pdb
• NMR Information: BMRB: 5881
• Descriptor: Mu-conotoxin SmIIIA (1 entity in total)
• Functional Keywords: mu-conotoxin, toxin
• Biological source: Conus stercusmuscarum (Fly-specked cone)
• Total number of polymer chains: 1
• Total formula weight: 2620.02

Authors

Keizer, D.W.,West, P.J.,Lee, E.F.,Olivera, B.M.,Bulaj, G.,Yoshikami, D.,Norton, R.S. (deposition date: 2003-07-24, release date: 2004-02-24, Last modification date: 2024-11-20)

Primary citation

Keizer, D.W.,West, P.J.,Lee, E.F.,Yoshikami, D.,Olivera, B.M.,Bulaj, G.,Norton, R.S.
Structural basis for tetrodotoxin-resistant sodium channel binding by mu-conotoxin SmIIIA.
J.Biol.Chem., 278:46805-46813, 2003

PubMed Abstract: 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.

PubMed: 12970353
DOI: 10.1074/jbc.M309222200

Experimental method

SOLUTION NMR