Novel Conantokins from Conus parius Venom Are Specific Antagonists of N-Methyl-D-aspartate Receptors

Teichert, Russell W.; Jimenéz, Elsie C.; Twede, Vernon; Watkins, Maren; Hollmann, Michael; Bułaj, Grzegorz; Olivera, Baldomero M.

doi:10.1074/jbc.m706611200

Cited by 43 publications

(80 citation statements)

References 23 publications

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“…Conantokin-G is 20-fold more potent on GluN2A and GluN2B-containing NMDA receptors than on GluN2C and GluN2D-containing receptors (Wittekindt et al, 2001;Sheng et al, 2007;Teichert et al, 2007), and conantokin-Br is more potent for the GluN2D-containing NMDA receptors than other conantokins (Table 11) (Twede et al, 2009). Although conantokin-G binds within the GluN2 ligand binding pocket, one molecular determinant of specificity of conantokin-G for GluN2B has been identified as a Met739 residue outside of the binding pocket within the D2 domain of the LBD.…”

Section: Glun2mentioning

confidence: 99%

Glutamate Receptor Ion Channels: Structure, Regulation, and Function

et al. 2010

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Section: Glun2mentioning

confidence: 99%

Glutamate Receptor Ion Channels: Structure, Regulation, and Function

et al. 2010

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“…Electrophysiology-The Xenopus oocyte expression system was used to study the effect of the CPY peptides on K ϩ and Na ϩ channels (14) and the N-methyl-D-aspartate receptor (15). In K ϩ channel assays, oocytes were treated, and channels were expressed as described (16).…”

Section: Extraction and Fractionation Of C Planorbis Venom-snailsmentioning

confidence: 99%

Tyrosine-rich Conopeptides Affect Voltage-gated K+ Channels

Imperial

Chen

Sporning

et al. 2008

Journal of Biological Chemistry

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Two venom peptides, CPY-Pl1 (EU000528) and CPY-Fe1 (EU000529), characterized from the vermivorous marine snails Conus planorbis and Conus ferrugineus, define a new class of conopeptides, the conopeptide Y (CPY) family. The peptides have no disulfide cross-links and are 30 amino acids long; the high content of tyrosine is unprecedented for any native gene product. The CPY peptides were chemically synthesized and shown to be biologically active upon injection into both mice and Caenorhabditis elegans; activity on mammalian Kv1 channel isoforms was demonstrated using an oocyte heterologous expression system, and selectivity for Kv1.6 was found. NMR spectroscopy revealed that the peptides were unstructured in aqueous solution; however, a helical region including residues 12-18 for one peptide, CPY-Pl1, formed in trifluoroethanol buffer. Clones obtained from cDNA of both species encoded prepropeptide precursors that shared a unique signal sequence, indicating that these peptides are encoded by a novel gene family. This is the first report of tyrosine-rich bioactive peptides in Conus venom.The venom of marine gastropods in the genus Conus has yielded numerous structurally and functionally diverse peptidic components (1). The increasing variety of bioactive peptides identified in cone snail venoms has provided insight into the seemingly endless variety of directions taken by Conus species in evolving neuroactive molecules to suit their diverse biological purposes.The bioactive peptides in Conus ("conopeptides") are classified into two broad groups: the non-disulfide-rich and the disulfide-rich (1). The latter are conventionally called conotoxins. The non-disulfide-rich class includes conopeptides with no cysteines (contulakins (2), conantokins (3), and conorfamides (4)) and conopeptides with two cysteines forming a single disulfide bond (conopressins (5) and contryphans (6)). The conopeptides that compose the disulfide-rich class have two or more disulfide bonds (1); among the major classes of molecular targets identified for these structurally diverse conopeptides are members of the voltage-gated and ligand-gated ion channel superfamilies.In this work, we present the discovery and characterization of a novel class of peptides, which we designate the conopeptide Y (CPY) 2 family, from the marine snails Conus planorbis and Conus ferrugineus (see Fig. 1). Both of these species belong to a distinct clade of Conus (7, 8). The first two peptides (9) belonging to the CPY family have a high frequency of tyrosine residues, in addition to basic and hydrophobic residues. The peptides are shown to be biologically active when injected into mouse and the nematode Caenorhabditis elegans. Activity on the Kv1 channel subfamily is demonstrated, and the subtype selectively within the subfamily is defined. EXPERIMENTAL PROCEDURES Extraction and Fractionation of C. planorbis Venom-Snailswere collected in Cebu and Marinduque Islands, Philippines, and dissected. Venom was pressed out of freshly dissected venom ducts that were kept on ice. V...

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“…Most adopt helical conformations in the presence of divalent cations. However, there are a few known conantokins that are inherently helical due to ␥-carboxyglutamate residue 7 being replaced with lysine; examples include conRl-A, conPr-C, and conT (26,27,47). Other elements that have been shown to contribute to conantokin structure are disulfide bridges; examples include conR and conP (48,49), although structural analysis of conR showed that the C-terminal disulfide bridge actually disrupted, rather than stabilized, ␣-helical content (25).…”

Section: Discussionmentioning

confidence: 99%

“…Subtracting the CD signal of the buffer from the peptide CD signal eliminated the contribution of the buffer to the peptide CD signal. The spectral intensities were expressed as mean residue ellipticities using the equation reported elsewhere (27), and a molar ellipticity of Ϫ35086.66 degrees cm 2 dmol Ϫ1 was estimated to be a perfect ␣-helix (100% ␣-helix). The percentage of helical conformation was calculated by assuming a linear relationship in comparison with 100% ␣-helicity.…”

mentioning

confidence: 99%

Stapling Mimics Noncovalent Interactions of γ-Carboxyglutamates in Conantokins, Peptidic Antagonists of N-Methyl-d-Aspartic Acid Receptors

Platt

Han

Green

et al. 2012

Journal of Biological Chemistry

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Background: Can dicarba bridges (stapling) replace noncovalent interactions that stabilize helical conformation of neuroactive peptides? Results: A rational design, synthesis, structural, and functional characterization of stapled conG analogs that target NMDA receptors is reported. Conclusion: Stapled conG analogs are potent antagonists of NMDA receptors and anticonvulsant compounds. Significance: Stapling can be successfully applied to convert neuroactive peptides into drug leads.

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Novel Conantokins from Conus parius Venom Are Specific Antagonists of N-Methyl-D-aspartate Receptors

Cited by 43 publications

References 23 publications

Glutamate Receptor Ion Channels: Structure, Regulation, and Function

Glutamate Receptor Ion Channels: Structure, Regulation, and Function

Tyrosine-rich Conopeptides Affect Voltage-gated K+ Channels

Stapling Mimics Noncovalent Interactions of γ-Carboxyglutamates in Conantokins, Peptidic Antagonists of N-Methyl-d-Aspartic Acid Receptors

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