A Consensus Structure for ω-Conotoxins with Different Selectivities for Voltage-sensitive Calcium Channel Subtypes: Comparison of MVIIA, SVIB and SNX-202

Nielsen, Katherine J.; Thomas, Linda; Lewis, Richard J.; Alewood, Paul F.; Craik, David J.

doi:10.1006/jmbi.1996.0576

Cited by 97 publications

(106 citation statements)

References 42 publications

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“…Biotinylation of Lys10 in the P/Q-selective MVIID significantly decreased binding affinity , and the importance of this residue for Ca v subtype selectivity was also confirmed by several independent studies Nielsen et al, 1996). The residue at position 10 is consistently a lysine in -conotoxins with high affinity for Ca v 2.1, but often an arginine or hydroxyproline in Ca v 2.2-selective peptides Nielsen et al, 1996). However, it remains to be determined if the subtype selectivity of Ca v 2.1-selective MVIIC and MVIID are significantly altered by a K10R swap.…”

Section: B Structure-activity Relationshipssupporting

confidence: 52%

“…Loop 4 residues with a significant effect on -conotoxin affinity include Arg21 in MVIIA and Arg17, Tyr22, and Lys24 in GVIA, whereas the residue at position 10 in loop 2 seems to play a key role in determining subtype selectivity (Nielsen et al, 1999a). Biotinylation of Lys10 in the P/Q-selective MVIID significantly decreased binding affinity , and the importance of this residue for Ca v subtype selectivity was also confirmed by several independent studies Nielsen et al, 1996). The residue at position 10 is consistently a lysine in -conotoxins with high affinity for Ca v 2.1, but often an arginine or hydroxyproline in Ca v 2.2-selective peptides Nielsen et al, 1996).…”

Section: B Structure-activity Relationshipsmentioning

confidence: 66%

“…It is now appreciated that -conotoxins represent some of the most selective known inhibitors for the neuronal Ca v isoforms 2.2 and 2.1. Specifically, -conotoxins CVID, CVIE, CVIF, GVIA, and MVIIA are particularly selective for Ca v 2.2, whereas MVIIC and MVIID show a preference for Ca v 2.1 underlying P/Q-type calcium currents (Monje et al, 1993;Woppmann et al, 1994;Nadasdi et al, 1995;Nielsen et al, 1996;Flinn et al, 1999;Lewis et al, 2000;Berecki et al, 2010). The binding site of -conotoxins to the Ca v subtypes has been mapped primarily to the external vestibule of the channel in the domain III S5-S6 region (Ellinor et al, 1994), consistent with preliminary results obtained from docking of -MVIIA to a homology model of Ca v 2.2 ( Fig.…”

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confidence: 99%

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Conus Venom Peptide Pharmacology

Lewis¹,

Dutertre²,

Vetter³

et al. 2012

Pharmacol Rev

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Section: B Structure-activity Relationshipssupporting

confidence: 52%

Section: B Structure-activity Relationshipsmentioning

confidence: 66%

mentioning

confidence: 99%

See 1 more Smart Citation

Conus Venom Peptide Pharmacology

Lewis¹,

Dutertre²,

Vetter³

et al. 2012

Pharmacol Rev

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393

424

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“…In that case, it is known that loop 2 is critical for high affinity binding to voltagegated calcium channels. Broadening of peaks from residues 11-13 suggested slow conformational exchange (42), and this was also supported by NMR relaxation measurements (46). It has been suggested that this conformational exchange may have functional significance and may allow MVIIA to bind to two different receptor subtypes in the molluscs that it preys upon (46).…”

Section: Fig 11 Depolarization-activated Camentioning

confidence: 70%

“…In particular, both the -and ␦-conotoxins contain a cystine knot motif (41,42), and a comparison of the structures of members of these families with MrVIB is shown in Fig. 9.…”

Section: Discussionmentioning

confidence: 99%

Structures of μO-conotoxins from Conus marmoreus

Daly

Ekberg

Thomas

et al. 2004

Journal of Biological Chemistry

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The O-conotoxins are an intriguing class of conotoxins targeting various voltage-dependent sodium channels and molluscan calcium channels. In the current study, we have shown MrVIA and MrVIB to be the first known peptidic inhibitors of the transient tetrodotoxinresistant (TTX-R) Na ؉ current in rat dorsal root ganglion neurons, in addition to inhibiting tetrodotoxinsensitive Na ؉ currents. Human TTX-R sodium channels are a therapeutic target for indications such as pain, highlighting the importance of the O-conotoxins as potential leads for drug development. Furthermore, we have used NMR spectroscopy to provide the first structural information on this class of conotoxins. MrVIA and MrVIB are hydrophobic peptides that aggregate in aqueous solution but were solubilized in 50% acetonitrile/water. The three-dimensional structure of MrVIB consists of a small ␤-sheet and a cystine knot arrangement of the three-disulfide bonds. It contains four backbone "loops" between successive cysteine residues that are exposed to the solvent to varying degrees. The largest of these, loop 2, is the most disordered part of the molecule, most likely due to flexibility in solution. This disorder is the most striking difference between the structures of MrVIB and the known ␦-and -conotoxins, which along with the O-conotoxins are members of the O superfamily. Loop 2 of -conotoxins has previously been shown to contain residues critical for binding to voltage-gated calcium channels, and it is interesting to speculate that the flexibility observed in MrVIB may accommodate binding to both sodium and molluscan calcium channels.

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Conformational and functional variability supported by the BPTI fold: Solution structure of the Ca2+ channel blocker calcicludine

Gilquin¹,

Lecoq²,

Desné³

et al. 1999

Proteins

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Calcicludine, a 60-amino acid protein isolated from the green mamba venom, has been recently identified as blocking a large set (i.e., L-, N- and P-type) of Ca2+ channels. The three-dimensional structure of calcicludine has been determined by NMR and molecular modeling using a data set of 723 unambiguous and 265 ambiguous distance restraints, as 33 phi and 13 chi1 dihedral angle restraints. Analysis of the 15 final structures (backbone root-mean-square deviation = 0.6 A) shows that calcicludine adopts the Kunitz-type protease inhibitor fold. Its three-dimensional structure is similar to that of snake K+ channel blockers dendrotoxins. Conformational differences with protease inhibitors and dendrotoxins are localized in the 3(10) helix and loop 1 (segments 1-7 and 10-19), the extremity of the beta-hairpin (segment 27-30), and loop 2 (segment 39-44). These regions correspond to the functional sites of bovine pancreatic trypsin inhibitor (BPTI) and dendrotoxins. The positioning of the N-terminal segment 1-7 relative to the rest of the protein is characteristic of calcicludine. The involvement of this segment and the positively charged K31 at the tip of the beta-hairpin in the biological activity of calcicludine is discussed.

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A Consensus Structure for ω-Conotoxins with Different Selectivities for Voltage-sensitive Calcium Channel Subtypes: Comparison of MVIIA, SVIB and SNX-202

Cited by 97 publications

References 42 publications

Conus Venom Peptide Pharmacology

Conus Venom Peptide Pharmacology

Structures of μO-conotoxins from Conus marmoreus

Conformational and functional variability supported by the BPTI fold: Solution structure of the Ca2+ channel blocker calcicludine

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