1oaw Citations

Three-dimensional solution structure of the calcium channel antagonist omega-agatoxin IVA: consensus molecular folding of calcium channel blockers.

J. Mol. Biol. 250 659-71 (1995)
Cited: 41 times
EuropePMC logo PMID: 7623383

Abstract

The three-dimensional solution structure of omega-agatoxin IVA, which is a specific blocker of the P-type calcium channel isolated from funnel web spider venom and has a molecular mass of 5.2 kDa, was determined by two dimensional 1H NMR spectroscopy, combined with simulated annealing calculations. On the basis of 563 experimental constraints, including 516 distance constraints obtained from the nuclear Overhauser effect, 21 torsion angle (phi, chi 1) constraints, and 26 constraints associated with hydrogen bonds and disulfide bonds, a total of 14 converged structures were obtained. The atomic root mean square difference for the 14 converged structures with respect to the mean coordinates is 0.42 (+/- 0.07) A for the backbone atoms (N, C alpha, C) and 0.95 (+/- 0.15) A for all heavy atoms of the central part (residues 4 to 38) constrained by four disulfide bonds. The N- and C-terminal segments (residues 1 to 3 and 39 to 48, respectively) have a disordered structure in aqueous solution. The molecular structure of omega-agatoxin IVA is composed of a short triple-stranded antiparallel beta-sheet, three loops, and the disordered N- and C-terminal segments. The overall beta-sheet topology is +2x, -1, which is the same as that reported for omega-conotoxin GVIA, an N-type calcium channel blocker. Irrespective of differences in the number of disulfide bonds and low primary sequence homology, these two peptide toxins show a significant structural similarity in three dimensions. The whole-cell voltage-clamp recording using rat cerebellar slices suggests that the hydrophobic C-terminal segment of omega-agatoxin IVA, which does not exist in omega-conotoxin GVIA, plays a crucial role in the blocking action of omega-agatoxin IVA on the P-type calcium channel in rat cerebellar Purkinje cells. The present study provides a molecular basis for the toxin-channel interaction, and thereby provides insight into the discrimination of different subtypes of calcium channels.

Articles - 1oaw mentioned but not cited (3)



Reviews citing this publication (13)

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  14. Solution structure of hpTX2, a toxin from Heteropoda venatoria spider that blocks Kv4.2 potassium channel. Bernard C, Legros C, Ferrat G, Bischoff U, Marquardt A, Pongs O, Darbon H. Protein Sci. 9 2059-2067 (2000)
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  17. Conformational and functional variability supported by the BPTI fold: solution structure of the Ca2+ channel blocker calcicludine. Gilquin B, Lecoq A, Desné F, Guenneugues M, Zinn-Justin S, Ménez A. Proteins 34 520-532 (1999)
  18. Adenosine A(1)-receptor-mediated tonic inhibition of glutamate release at rat hippocampal CA3-CA1 synapses is primarily due to inhibition of N-type Ca(2+) channels. Manita S, Kawamura Y, Sato K, Inoue M, Kudo Y, Miyakawa H. Eur. J. Pharmacol. 499 265-274 (2004)
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  22. Solution structure of agelenin, an insecticidal peptide isolated from the spider Agelena opulenta, and its structural similarities to insect-specific calcium channel inhibitors. Yamaji N, Sugase K, Nakajima T, Miki T, Wakamori M, Mori Y, Iwashita T. FEBS Lett. 581 3789-3794 (2007)
  23. Sequence-specific assignment of 1H-NMR resonance and determination of the secondary structure of Jingzhaotoxin-I. Zeng XZ, Zhu Q, Liang SP. Acta Biochim. Biophys. Sin. (Shanghai) 37 567-572 (2005)
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