1ryv

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Three dimensional solution structure of the K27A MUTANT of sodium channels inhibitor HAINANTOXIN-IV BY 2D 1H-NMR

Overview

Hainantoxin-IV (HNTX-IV) can specifically inhibit the neuronal, tetrodotoxin-sensitive sodium channels and defines a new class of, depressant spider toxin. The sequence of native HNTX-IV is, ECLGFGKGCNPSNDQCCKSSNLVCSRKHRWCKYEI-NH(2). In the present study, to obtain, further insight into the primary and tertiary structural requirements of, neuronal sodium channel blockers, we determined the solution structure of, HNTX-IV as a typical inhibitor cystine knot motif and synthesized four, mutants designed based on the predicted sites followed by structural, elucidation of two inactive mutants. Pharmacological studies indicated, that the S12A and R26A mutants had activities near that of native HNTX-IV, while K27A and R29A demonstrated activities reduced by 2 orders of, magnitude. (1)H MR analysis showed the similar molecular conformations for, native HNTX-IV and four synthetic mutants. Furthermore, in the determined, structures of K27A and R29A, the side chains of residues 27 and 29 were, located in the identical spatial position to those of native HNTX-IV., These results suggested that residues Ser(12), Arg(26), Lys(27), and, Arg(29) were not responsible for stabilizing the distinct conformation of, HNTX-IV, but Lys(27) and Arg(29) were critical for the bioactivities. The, potency reductions produced by Ala substitutions were primarily due to the, direct interaction of the essential residues Lys(27) and Arg(29) with, sodium channels rather than to a conformational change. After comparison, of these structures and activities with correlated toxins, we hypothesized, that residues Lys(27), Arg(29), His(28), Lys(32), Phe(5), and Trp(30), clustered on one face of HNTX-IV were responsible for ligand binding.

About this Structure

1RYV is a Single protein structure of sequence from [1] with NH2 as ligand. Full crystallographic information is available from OCA.

Reference

Structure--activity relationships of hainantoxin-IV and structure determination of active and inactive sodium channel blockers., Li D, Xiao Y, Xu X, Xiong X, Lu S, Liu Z, Zhu Q, Wang M, Gu X, Liang S, J Biol Chem. 2004 Sep 3;279(36):37734-40. Epub 2004 Jun 16. PMID:15201273

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