<i>Conus</i>Peptides: Biodiversity-based Discovery and Exogenomics

Olivera, Baldomero M.

doi:10.1074/jbc.r600020200

Cited by 267 publications

(196 citation statements)

References 34 publications

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“…Venoms from cone snails provide interesting libraries of peptide toxins displaying a high affinity for voltage-or ligand-gated ion channels and have been successfully used as structural probes to characterize nAChRs [9,46,47]. α-conotoxins, that specifically target nAChRs, display a consensus fold with a central helical region braced by two conserved disulphide bridges ( Figure 7).…”

Section: Investigating Switches In Nachr Selectivity Between Differenmentioning

confidence: 99%

“…This rigidity together with the diversity in amino acid composition displayed by α-conotoxins ensures their unique selectivity for different nAChR subtypes. These conotoxins have been classified into different families (α3/5, α4/3, α4/6 and α4/7) based on the number of residues between the second and third cysteine residues and between the third and fourth cysteines [46]. Page …”

Section: Investigating Switches In Nachr Selectivity Between Differenmentioning

confidence: 99%

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Insight in nAChR subtype selectivity from AChBP crystal structures

Rucktooa

Smit²,

Sixma

2009

Biochemical Pharmacology

119

118

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Nicotinic acetylcholine receptors (nAChRs) display a broad variety of subtypes, which in turn present a complex subcellular and regional expression pattern in the brain, as well as a specific pharmacological profile. The association of these nAChRs with different types of brain disease has turned them into interesting drug targets for the treatment of Alzheimer's disease or schizophrenia, or for anti-smoking compounds among others. In the same way, muscle-type nAChRs present at neuromuscular junctions are also being targeted by muscle relaxants. However, to date no high-resolution structural data is available on functional

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Section: Investigating Switches In Nachr Selectivity Between Differenmentioning

confidence: 99%

Section: Investigating Switches In Nachr Selectivity Between Differenmentioning

confidence: 99%

Insight in nAChR subtype selectivity from AChBP crystal structures

Rucktooa

Smit²,

Sixma

2009

Biochemical Pharmacology

119

118

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“…Many of these peptides are disulfide-rich neurotoxins, termed conotoxins, that selectively inhibit ligandand voltage-gated ion channels. This high selectivity of conotoxins has lead to a great interest in the use of these molecules as pharmacological tools and the design of novel therapeutics [1,37].…”

Section: Introductionmentioning

confidence: 99%

“…The primary structures of more than 100 conotoxins have been determined and classified into gene superfamilies on the basis of the amino acid sequences of the signal peptides of their precursors [37]. In general, the members of each superfamily have a characteristic arrangement of cysteine residues.…”

Section: Introductionmentioning

confidence: 99%

α4/7-conotoxin Lp1.1 is a novel antagonist of neuronal nicotinic acetylcholine receptors

et al. 2008

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Cone snails comprise approximately 500 species of venomous molluscs which have evolved the ability to generate multiple toxins with varied and exquisite selectivity. α-Conotoxin is a powerful tool for defining the composition and function of nicotinic acetylcholine receptors which play a crucial role in excitatory neurotransmission and are important targets for drugs and insecticides. An α4/7 conotoxin, Lp1.1, originally identified by cDNA and genomic DNA cloning from Conus leopardus, was found devoid of the highly conserved Pro residue in the first intercysteine loop. To further study this toxin, α-Lp1.1 was chemically synthesized and refolded into its globular disulfide isomer. The synthetic Lp1.1 induced seizure and paralysis on freshwater goldfish and selectively reversibly inhibited ACh-evoked currents in Xenopus oocytes expressing rat α3β2 and α6α3β2 nAChRs. Comparing the distinct primary structure with other functionally related α-conotoxins could indicate structural features in Lp1.1 that may be associated with its unique receptor recognition profile.

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“…Accordingly, we have examined several members of the large family of conus snail toxins for selectivity to the Lymnaea, Aplysia and Bulinus binding proteins [11,[19][20][21]. Many toxins also show considerable selectivity for the three binding proteins (Table I) [22,23].…”

Section: Structural Determinants Of Specificitymentioning

confidence: 99%

Structure-guided drug design: Conferring selectivity among neuronal nicotinic receptor and acetylcholine-binding protein subtypes

Taylor

Talley

Radić

et al. 2007

Biochemical Pharmacology

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Neuronal nicotinic receptors, encoded by nine genes of the alpha and three of the beta type of subunits, and whose gene products assemble in distinct permutations as pentameric molecules, constitute a fertile area for structure-guided drug design. Design strategies are augmented by a wide variety of peptide, alkaloid and terpenoid toxins from various marine and terrestrial species that interact with nicotinic receptors. Also, acetylcholinebinding proteins from mollusks, as structural surrogates of the receptor that mimic its extracellular domain, provide atomic resolution templates for analysis of structure and response. Herein, we describe a structure-guided approach to nicotinic ligand design that employs crystallography of this protein as the basic template, but also takes into consideration the dynamic properties of the receptor molecules in their biological media. We present the crystallographic structures of several complexes of various agonists and antagonists that associate with the agonist site and can competitively block the action of acetylcholine. In so far as the extracellular domain is involved, we identify additional noncompetitive sites at those subunit interfaces where agonists do not preferentially bind. Ligand association at these interface sites may modulate receptor function. Ligand binding is also shown by solution-based spectroscopic and spectrometric methods to affect the dynamics of discrete domains of the receptor molecule. The surrogate receptor molecules can then be employed to design ligands selective for receptor subtype through the novel methods of freeze-frame, click chemistry that uses the very structure of the target molecule as a template for synthesis of the inhibitor.

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ConusPeptides: Biodiversity-based Discovery and Exogenomics

Cited by 267 publications

References 34 publications

Insight in nAChR subtype selectivity from AChBP crystal structures

Insight in nAChR subtype selectivity from AChBP crystal structures

α4/7-conotoxin Lp1.1 is a novel antagonist of neuronal nicotinic acetylcholine receptors

Structure-guided drug design: Conferring selectivity among neuronal nicotinic receptor and acetylcholine-binding protein subtypes

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