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At least 235 records · Page 13Linked to original sources
PubMed1989

Solution conformation of conotoxin GI determined by 1H nuclear magnetic resonance spectroscopy and distance geometry calculations.

Conformational analysis of conotoxin GI, one of the neurotoxic peptides produced by a marine snail, genus Conus, was performed by a combination of nuclear magnetic resonance spectroscopy (NMR) and distance geometry calculations. The resulting conformers on minimization of the target function were classified into two groups. The difference in the structures of the conformers is mainly due to the difference in the orientation of the side chain of the tyrosyl residue. The results show that the solution structure of conotoxin GI satisfies the conformational requirements for the biological activity of an antagonist toward nicotinic cholinergic receptors elucidated in a series of studies on alkaloids. The structure is discussed on the basis of the results of comparison of the atomic arrangements of the active sites of snake venom peptides and molecular models based on the results of secondary structure prediction.

Amino Acid Sequence↗
PubMed2006

Definition and characterization of the short alphaA-conotoxins: a single residue determines dissociation kinetics from the fetal muscle nicotinic acetylcholine receptor.

We report the definition and characterization of a conotoxin subfamily, designated the short alphaA-conotoxins (alphaA(S)) and demonstrate that all of these share the unique property of selectively antagonizing the fetal subtype of the mammalian neuromuscular nicotinic acetylcholine receptor (nAChR). We have characterized newly identified alphaA(S)-conotoxins from Conus pergrandis and have conducted a more detailed characterization of alphaA-conotoxins previously reported from additional Conus species. Among the results, the characterization of the short alphaA-conotoxins revealed diverse kinetics of a block of the fetal muscle nAChR, particularly in dissociation rates. The structure-function relationships of native alphaA(S)-conotoxins and some analogues revealed a single amino acid locus (alternatively either His or Pro in native peptides) that is a critical determinant of the dissociation kinetics. The unprecedented binding selectivity for the fetal muscle nAChR, coupled with the kinetic diversity, should make alphaA(S)-conotoxins useful ligands for a diverse set of studies. The rapidly reversible peptides may be most suitable for electrophysiological studies, while the relatively irreversible peptides should be most useful for binding and localization studies.

Amino Acid Sequence↗
PubMed1999

NMR solution structure of alpha-conotoxin ImI and comparison to other conotoxins specific for neuronal nicotinic acetylcholine receptors.

Alpha-Conotoxins, peptides produced by predatory species of Conus marine snails, are potent antagonists of nicotinic acetylcholine receptors (nAChRs), ligand-gated ion channels involved in synaptic transmission. We determined the NMR solution structure of the smallest known alpha-conotoxin, ImI, a 12 amino acid peptide that binds specifically to neuronal alpha7-containing nAChRs in mammals. Calculation of the structure was based on a total of 80 upper distance constraints and 31 dihedral angle constraints resulting in 20 representative conformers with an average pairwise rmsd of 0.44 A from the mean structure for the backbone atoms N, Calpha, and C' of residues 2-11. The structure of ImI is characterized by two compact loops, defined by two disulfide bridges, which form distinct subdomains separated by a deep cleft. Two short 310-helical regions in the first loop are followed by a C-terminal beta-turn in the second. The two disulfide bridges and Ala 9 form a rigid hydrophobic core, orienting the other amino acid side chains toward the surface. Comparison of the three-dimensional structure of ImI to those of the larger, 16 amino acid alpha-conotoxins PnIA, PnIB, MII, and EpI-also specific for neuronal nAChRs-reveals remarkable similarity in local backbone conformations and relative solvent-accessible surface areas. The core scaffold is conserved in all five conotoxins, whereas the residues in solvent-exposed positions are highly variable. The second helical region, and the specific amino acids that the helix exposes to solvent, may be particularly important for binding and selectivity. This comparative analysis provides a three-dimensional structural basis for interpretation of mutagenesis data and structure-activity relationships for ImI as well other neuronal alpha-conotoxins.

Amino Acid Sequence↗
PubMed2006

Solution structures of two structural isoforms of CMrVIA chi/lambda-conotoxin.

alpha-Conotoxins possess a conserved four-cysteine framework and disulfide linkages (C(1)(-)(3), C(2)(-)(4)) that fold toward the globular conformation with absolute fidelity. Despite the presence of a similar conserved set of cysteine framework, chi/lambda-conotoxins adopt an alternate disulfide-pairing (C(1)(-)(4), C(2)(-)(3)) and its consequent ribbon conformation, exhibiting distinct biological activities from alpha-conotoxins. chi/lambda-Conotoxin CMrVIA (VCCGYKLCHOC-COOH) isolated from the venom of Conus marmoreus natively exists in the ribbon conformation and induces seizures in mice at a potency that is of three orders higher than the non-native globular form. We have chemically synthesized two isoforms of CMrVIA conotoxin in the ribbon and globular conformation and determined their structures by (1)H NMR spectroscopy. The ribbon (PDB ID 2B5P) and globular conformations (PBD ID 2B5Q) were calculated to have paired-wise backbone RMSDs of 0.48 +/- 0.1 and 0.58 +/- 0.1 A respectively. Unlike the native globular alpha-conotoxins, the globular canonical form of CMrVIA chi/lambda-conotoxin exhibited heterogeneity in its solution structure as noted by the presence of minor conformers and poorer RMSD of structure calculation. Paired-wise backbone comparison between the native ribbon and the non-native globular form of CMrVIA conotoxin revealed an RMSD of 4.73 A, emphasizing their distinct conformational differences. These structural data are essential for the understanding of the structure-function activity of chi/lambda-conotoxins, as well as unraveling the folding propensities of these short peptide toxins.

Animals↗
PubMed2005

Patterns of cladogenesis in the venomous marine gastropod genus Conus from the Cape Verde islands.

Isolated oceanic archipelagos are excellent model systems to study speciation, biogeography, and evolutionary factors underlying the generation of biological diversity. Despite the wealth of studies documenting insular speciation, few of them focused on marine organisms. Here, we reconstruct phylogenetic relationships among species of the marine venomous gastropod genus Conus from the Cape Verde archipelago. This small island chain located in the Central Atlantic hosts 10% of the worldwide species diversity of Conus. Analyses were based on mtDNA sequences, and a novel nuclear marker, a megalin-like protein, member of the low-density lipoprotein receptor gene family. The inferred phylogeny recovered two well-defined clades within Conus. One includes Cape Verde endemic species with larger shells, known as the "venulatus" complex together with C. pulcher from the Canary Islands. The other is composed of Cape Verde endemic and West Africa and Canary Island "small" shelled species. In both clades, nonendemic Conus were resolved as sister groups of the Cape Verde endemics, respectively. Our results indicate that the ancestors of "small" and "large" shelled lineages independently colonized Cape Verde. The resulting biogeographical pattern shows the grouping of most Cape Verde endemics in monophyletic island assemblages. Statistical tests supported a recent radiation event within the "small shell" clade. Using a molecular clock, we estimated that the colonization of the islands by the "small" shelled species occurred relatively close to the origin of the islands whereas the arrival of "large" shelled Conus is more recent. Our results suggest that the main factor responsible for species diversity in the archipelago may be allopatric speciation promoted by the reduced dispersal capacity of nonplanktonic lecithotrophic larvae.

Africa, Western↗
PubMed2006

Novel O-superfamily conotoxins identified by cDNA cloning from three vermivorous Conus species.

The O-superfamily of conotoxins includes several subfamilies with different pharmacological targets, all of which are voltage-gated ion channels and distributed widely in varied Conus species. The venom components from any Conus species are quite distinct from those of other species. Seven novel O-superfamily peptides were identified by cDNA cloning from the three vermivorous Conus species of C. betulinus, C. lividus and C. caracteristicus native to Hainan. They share three common signal sequences, and a conserved arrangement of cysteine residues (C-C-CC-C-C). Phylogenetic analysis of newly found conotoxins in this study and known homologue O-superfamily sequences from the other Conus species was performed systematically. Divergence and percentage identity of the amino acid sequences of the signal regions suggest that the novel conotoxins described in this investigation belong to the three broad clades: MSGL, ME-QK and MKLT, each of which has its own characteristic signature signal sequence and cysteine codon conservation. Relative to this work, it is noted that O-superfamily conotoxins are not well represented from vermivorous species. The elucidated cDNAs of these newly found vermivorous toxins would facilitate a better understanding for basic research and drug discovery.

Animals↗
PubMed2006

Animal toxins as analgesics--an overview.

Pain is a multidimensional sensory experience, and multiple mechanisms are involved in the generation of pathophysiological nociceptive pain. Identification of the mechanisms and molecular components responsible for pain generation has not only advanced our understanding of pain and its control, but has also led to the selection of new targets for designing novel analgesic drugs. The high selectivity and specificity of animal toxins have enabled their use as potential therapeutics in the treatment of pain and candidates for the development of new analgesic drugs. This review focuses on the use of animal toxins for pain control and examines the possible analgesic mechanisms of these molecules.

Analgesics↗
PubMed2005

Association/dissociation of a channel-kinase complex underlies state-dependent modulation.

Although ion channels are regulated by protein kinases, it has yet to be established whether the behavioral state of an animal may dictate whether or not modulation by a kinase can occur. Here, we describe behaviorally relevant changes in the ability of a nonselective cation channel from Aplysia bag cell neurons to be regulated by protein kinase C (PKC). This channel drives a prolonged afterdischarge that triggers the release of egg-laying hormone and a series of reproductive behaviors. The afterdischarge is followed by a lengthy refractory period, during which additional bursting cannot be elicited. Previously, we reported that, in excised inside-out patches, the cation channel is closely associated with PKC, which increases channel activity. We now show that this channel-kinase association is plastic, because channels excised from certain neurons lack PKC-dependent modulation. Although direct application of PKC-activating phorbol ester to these patches had no effect, exposing the neurons themselves to phorbol ester reinstated modulation, suggesting that an absence of modulation was attributable to a lack of associated kinase. Furthermore, modulation was restored by pretreating neurons with either PP1 [4-amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine] or SU6656, inhibitors of Src tyrosine kinase, an enzyme whose Src homology 3 domain is required for channel-PKC association. Neurons that were stimulated to afterdischarge and had entered the prolonged refractory period were found to have more phosphotyrosine staining and less channel-PKC association than unstimulated neurons. These findings suggest that Src-dependent regulation of the association between the cation channel and PKC controls both the long-term excitability of these neurons and their ability to induce reproduction.

Adenosine Triphosphate↗