Solution structure of the calcium channel antagonist ω‐conotoxin GVIA

Skalicky, Jack J.; Cieśla, Daniel; Pardi, Arthur; Metzler, William J.; Galdes, Alphonse

doi:10.1002/pro.5560021005

Cited by 57 publications

(45 citation statements)

References 55 publications

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“…The interactions with the N-type calcium channel of GVIA and the structurally related MVIIA are probably similar. In the case of MVIIA, Arg 10 , Leu 11 , and Arg 21 are as important as Lys 2 and Tyr 13 for the affinity of MVIIA for the N-type calcium channel, although it should be noted that these conclusions were based on rat (25) and chick (44) brain binding data. Fig.…”

Section: Discussionmentioning

confidence: 99%

Structure-Function Relationships of ω-Conotoxin GVIA

Lew

Flinn

Pallaghy³

et al. 1997

Journal of Biological Chemistry

108

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The structure-function relationships of the N-type calcium channel blocker, -conotoxin GVIA (GVIA), have been elucidated by structural, binding and in vitro and in vivo functional studies of alanine-substituted analogues of the native molecule. Alanine was substituted at all non-bridging positions in the sequence. In most cases the structure of the analogues in aqueous solution was shown to be native-like by 1 H NMR spectroscopy. Minor conformational changes observed in some cases were characterized by two-dimensional NMR. Replacement of Lys 2 and Tyr 13 with Ala caused reductions in potency of more than 2 orders of magnitude in three functional assays (sympathetic nerve stimulation of rat isolated vas deferens, right atrium and mesenteric artery) and a rat brain membrane binding assay. Replacement of several other residues with Ala (particularly Arg 17 , Tyr 22 and Lys 24 ) resulted in significant reductions in potency (<100-fold) in the functional assays, but not the binding assay. The potencies of the analogues were strongly correlated between the different functional assays but not between the functional assays and the binding assay. Thus, the physiologically relevant assays employed in this study have shown that the high affinity of GVIA for the N-type calcium channel is the result of interactions between the channel binding site and the toxin at more sites than the previously identified Lys 2 and Tyr 13 .The fish-hunting marine cone snails produce a range of polypeptide toxins that rapidly immobilize their prey (1, 2). A number of such toxins targeted at ion channels have been isolated from the venoms of these cone shells, including several that selectively block N-and P-type calcium channels (3). The toxin studied here, -conotoxin GVIA (GVIA), 1 is a 27-residue polypeptide from Conus geographus (4) that selectively blocks N-type voltage-gated calcium channels (5, 6), an activity that may confer a number of useful therapeutic properties on GVIA, including antihypertensive, analgesic, and neuroprotective activities, as demonstrated for the closely related -conotoxin MVIIA (MVIIA) from Conus magus (7) .The amino acid sequence of GVIA (with the cystine bridges indicated by lines) is as show below.

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Section: Discussionmentioning

confidence: 99%

Structure-Function Relationships of ω-Conotoxin GVIA

Lew

Flinn

Pallaghy³

et al. 1997

Journal of Biological Chemistry

108

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“…Structures of two other og-conotoxins have been obtained to date: co-CgTx [4][5][6][7], and m-conotoxin MVIIC (og-CmTxc) [10][11] (for sequences see Table 3). The overall fold of these two molecules as well as og-CmTxa, is very similar.…”

Section: Comparison To Other Co-conotoxinsmentioning

confidence: 99%

“…One class of such peptides are the og-conotoxins that bind specifically to presynaptic voltagegated Ca 2+ channels, causing inhibition of neurotransmitter release, o~-Conotoxin GVIA (co-CgTx) from Conus geographus binds specifically to the N-type Ca z+ channels and has been essential in identifying and characterizing these channels [2,3]. Four independent NMR solution structures of this peptide have been determined recently [4][5][6][7]. o)-Conotoxin MVIIA (coCmTxa), from Conus magus, although having only 40% sequence homology to co-CgTx, has the same specificity and nearly the same apparent binding affinity as o)-CgTx to the N-type Ca 2+ channel [8].…”

Section: Introductionmentioning

confidence: 99%

Solution structure of ω‐conotoxin MVIIA using 2D NMR spectroscopy

Basus¹,

Nádasdi²,

Ramachandran³

et al. 1995

FEBS Letters

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The solution structure of ~-conotoxin MVIIA (SNX-111), a peptide toxin from the fish hunting cone snail Conus magus and a high-affinity blocker of N-type calcium channels, was determined by 2D NMR spectroscopy. The backbones of the best 44 structures match with an average pairwise RMSD of 0.59 angstroms. The structures contain a short segment of triplestranded t-sheet involving residues 6-8, 20-21, and 24-25. The structure of this toxin is very similar to that of ¢o-conotoxin GVIA with which is has only 40% sequence homology, but very similar calcium channel binding affinity and selectivity.

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“…The length of this hinge region may not affect the relative orientation of two [3-strands but may affect the CD spectral profiles. The three-dimensional structures of c0GVIA [9][10][11][12], toMVIIA [13][14][15], and coMVIIC [16,17] have been determined by NMR analysis. Despite differences in primary amino acid sequences, the polypeptide chain framework is conserved in all of the co-conotoxins.…”

Section: Discussionmentioning

confidence: 99%

Binding of chimeric analogs of ω‐conotoxin MVIIA and MVIIC to the N‐ and P/Q‐type calcium channels

et al. 1997

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Despite their high sequence homology, the peptide neurotoxins ¢o-conotoxin MVIIA and MVIIC selectively block N-and P/Q-type calcium channels, respectively. To study the recognition mechanism of calcium channel subtypes, two chimeric analogs of ¢o-conotoxin MVIIA and MVIIC were synthesized by exchanging their N-and C-terminal halves. Binding assay for both N-and P/Q-type calcium channels showed that amino acid residues restricted to the N-terminal half are important for the recognition of N-type channels, whereas essential residues for P/Q-type channel recognition are widely spread over the whole ¢o-conotoxin molecule.

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Solution structure of the calcium channel antagonist ω‐conotoxin GVIA

Cited by 57 publications

References 55 publications

Structure-Function Relationships of ω-Conotoxin GVIA

Structure-Function Relationships of ω-Conotoxin GVIA

Solution structure of ω‐conotoxin MVIIA using 2D NMR spectroscopy

Binding of chimeric analogs of ω‐conotoxin MVIIA and MVIIC to the N‐ and P/Q‐type calcium channels

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