α-Conotoxins

Arias, Hugo R.; Blanton, Michael P.

doi:10.1016/s1357-2725(00)00051-0

Cited by 69 publications

(62 citation statements)

References 59 publications

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“…Crude Venom Extraction-Specimens of C. vexillum (8), Conus mustelinus (7), Conus miles (9), and Conus capitaneus (10) were collected from the Great Barrier Reef, Australia. Crude extracts were prepared from venom duct material using 30% acetonitrile/water acidified with 0.1% trifluoroacetic acid.…”

Section: Methodsmentioning

confidence: 99%

“…Conotoxins acting at nAChRs include the ␣-conotoxin, ␣A-conotoxin, -conotoxin, and ␣S-conotoxin families. The ␣-conotoxins are a large family of well characterized competitive nAChR antagonists with diverse subtype selectivities that allow the pharmacological dissection of nAChR subtypes (1,8). The structurally different ␣A-conotoxins are competitive antagonists with specificity for muscle nAChRs but lack the selectivity for the ␣1/␦ interface that is exhibited by the 3/5 subfamily of ␣-conotoxins (7), whereas the -conotoxins are non-competitive antagonists at the muscle nAChR subtype (7).…”

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confidence: 99%

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Identification of a Novel Class of Nicotinic Receptor Antagonists

Loughnan

Nicke

Jones

et al. 2006

Journal of Biological Chemistry

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The venoms of predatory marine snails (Conus spp.) contain diverse mixtures of peptide toxins with high potency and selectivity for a variety of voltage-gated and ligand-gated ion channels. Here we describe the chemical and functional characterization of three novel conotoxins, ␣D-VxXIIA, ␣D-VxXIIB, and ␣D-VxXIIC, purified from the venom of Conus vexillum. Each toxin was observed as an ϳ11-kDa protein by LC/MS, size exclusion chromatography, and SDS-PAGE. After reduction, the peptide sequences were determined by Edman degradation chemistry and tandem MS. Combining the sequence data together with LC/MS and NMR data revealed that in solution these toxins are pseudo-homodimers of paired 47-50-residue peptides. The toxin subunits exhibited a novel arrangement of 10 conserved cystine residues, and additional post-translational modifications contributed heterogeneity to the proteins. Binding assays and two-electrode voltage clamp analyses showed that ␣D-VxXIIA, ␣D-VxXIIB, and ␣D-VxXIIC are potent inhibitors of nicotinic acetylcholine receptors (nAChRs) with selectivity for ␣7 and ␤2 containing neuronal nAChR subtypes. These dimeric conotoxins represent a fifth and highly divergent structural class of conotoxins targeting nAChRs. Nicotinic acetylcholine receptors (nAChRs)4 belong to the Cys-loop superfamily of pentameric ligand-gated ion channels. Neuronal nAChRs are generally formed from a combination of ␣ and ␤ subunits (␣2-␣10 and ␤2-␤4) that can assemble into a diversity of nAChR subtypes with different pharmacological and functional properties (1). Given their physiological importance, nAChRs are often targeted by venom peptides (2).Our current knowledge of the structure and function of nAChRs owes much to studies using snake toxins as biochemical or pharmacological tools to isolate and characterize this receptor (3). The "bungarotoxin" family of proteins in the venom of elapid and hydrophid snakes includes the -and ␣-neurotoxins, muscarinic toxins, cytotoxins, cardiotoxins, fasciculins, calciseptins, and mambins (4, 5). The structurally related short-chain and long-chain ␣-neurotoxins and the "weak non-conventional" snake toxins are comprised of 60 -74 amino acids, including 8 or 10 cystine residues and their structures have a three-fingered fold. The -and ␣-neurotoxins both inhibit nAChRs but differ in their specificity and binding kinetics (4).Conotoxins are small disulfide-rich peptide toxins found in the venom of predatory marine snails from the genus Conus. These venom peptides generally target a variety of voltage-gated and ligand-gated ion channels (6, 7). Conotoxins acting at nAChRs include the ␣-conotoxin, ␣A-conotoxin, -conotoxin, and ␣S-conotoxin families. The ␣-conotoxins are a large family of well characterized competitive nAChR antagonists with diverse subtype selectivities that allow the pharmacological dissection of nAChR subtypes (1,8). The structurally different ␣A-conotoxins are competitive antagonists with specificity for muscle nAChRs but lack the selectivity for the ␣1/␦ interface that is ex...

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Identification of a Novel Class of Nicotinic Receptor Antagonists

Loughnan

Nicke

Jones

et al. 2006

Journal of Biological Chemistry

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“…-Ctx discovery in conjunction with chemical peptide synthesis has provided an increasing array of biologically active compounds with varying subtype selectivity [13,14,[16][17][18][19][20][21][22][23]56]. Based on the observation that the residue at position 10 of the 4/7 class of -Ctxs can influence nAChR M a n u s c r i p t…”

Section: Discussionmentioning

confidence: 99%

“…-Conotoxins ( -Ctxs) range in size from 9 14 amino acids and have an affinity for a variety of nAChR subtypes. Their small size, rigid framework consisting of four-and seven-residue loops conferred by two disulfide bonds, and ease of synthesis make them ideal for structure function studies (Table 1) [17][18][19].…”

Section: Introductionmentioning

confidence: 99%

Hydrophobic residues at position 10 of α-conotoxin PnIA influence subtype selectivity between α7 and α3β2 neuronal nicotinic acetylcholine receptors

Hopping

Wang

Hogg³

et al. 2014

Biochemical Pharmacology

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Neuronal nicotinic acetylcholine receptors (nAChRs) are a diverse class of ligand-gated ion channels involved in neurological conditions such as neuropathic pain and Alzheimer's disease.-Conotoxin [A10L]PnIA is a potent and selective antagonist of the mammalian 7 nAChR with a key binding interaction at position 10. We now describe a molecular analysis of the receptorligand interactions that determine the role of position 10 in determining potency and selectivity for the 7 and 3 2 nAChR subtypes. Using electrophysiological and radioligand binding methods on a suite of [A10L]PnIA analogs we observed that hydrophobic residues in position 10 maintained potency at both subtypes whereas charged or polar residues abolished 7 binding.Molecular docking revealed dominant hydrophobic interactions with several 7 and 3 2 receptor residues via a hydrophobic funnel. Incorporation of norleucine (Nle) caused the largest (8-fold) increase in affinity for the 7 subtype (Ki = 44 nM) though selectivity reverted to 3 2 (IC 50 = 0.7 nM). It appears that that placement of a single methyl group determines selectivity between 7 and 3 2 nAChRs via different molecular determinants.

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“…These ␣-conotoxins are a series of structurally and functionally related peptides found in the venom of cone snail species. They are classified into subfamilies based on the number of residues in their two "loops" between conserved Cys residues, with 3/5 (CCX 3 CX 5 C), 4/3 (CCX 4 CX 3 C), and 4/7 (CCX 4 CX 7 C) subfamilies the most common (19). The toxins of Conus sp.…”

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confidence: 99%

Structure-Function Elucidation of a New α-Conotoxin, Lo1a, from Conus longurionis

Lebbe

Peigneur

Maiti

et al. 2014

Journal of Biological Chemistry

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Background: ␣-Conotoxins are small toxins produced by cone snails and antagonists of nicotinic acetylcholine receptors. Results: Two mutants were created to investigate the unusual C terminus of a novel ␣-conotoxin from Conus longurionis. Conclusion: We characterized an important residue for discrimination between neuronal and muscle subtype nicotinic acetylcholine receptors. Significance: This opens perspectives for designing new ligands to affect brain disorders.

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α-Conotoxins

Cited by 69 publications

References 59 publications

Identification of a Novel Class of Nicotinic Receptor Antagonists

Identification of a Novel Class of Nicotinic Receptor Antagonists

Hydrophobic residues at position 10 of α-conotoxin PnIA influence subtype selectivity between α7 and α3β2 neuronal nicotinic acetylcholine receptors

Structure-Function Elucidation of a New α-Conotoxin, Lo1a, from Conus longurionis

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