Conotoxin TVIIA, a novel peptide from the venom of Conus tulipa (original) (raw)

The three-dimensional solution structure of conotoxin TVIIA, a 30-residue polypeptide from the venom of the piscivorous cone snail Conus tulipa, has been determined using 2D 1 H NMR spectroscopy. TVIIA contains six cysteine residues which form a`four-loop' structural framework common to many peptides from Conus venoms including the v-, d-, k-, and mO-conotoxins. However, TVIIA does not belong to these well-characterized pharmacological classes of conotoxins, but displays high sequence identity with conotoxin GS, a muscle sodium channel blocker from Conus geographus. Structure calculations were based on 562 interproton distance restraints inferred from NOE data, together with 18 backbone and nine side-chain torsion angle restraints derived from spin-spin coupling constants. The final family of 20 structures had mean pairwise rms differences over residues 2±27 of 0.18^0.05 A Ê for the backbone atoms and 1.39^0.33 A Ê for all heavy atoms. The structure consists of a triple-stranded, antiparallel b sheet with 12x, 21 topology (residues 7±9, 16±20 and 23±27) and several b turns. The core of the molecule is formed by three disulfide bonds which form a cystine knot motif common to many toxic and inhibitory polypeptides. The global fold, molecular shape and distribution of amino-acid sidechains in TVIIA is similar to that previously reported for conotoxin GS, and comparison with other four-loop conotoxin structures provides further indication that TVIIA and GS represent a new and distinct subgroup of this structural family. The structure of TVIIA determined in this study provides the basis for determining a structureactivity relationship for these molecules and their interaction with target receptors.