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Structure and allosteric activity of a single-disulfide conopeptide from Conus zonatus at human α3β4 and α7 nicotinic acetylcholine receptors

Mohan, MK and Abraham, N and Rajesh, RP and Jayaseelan, BF and Ragnarsson, L and Lewis, RJ and Sarma, SP (2020) Structure and allosteric activity of a single-disulfide conopeptide from Conus zonatus at human α3β4 and α7 nicotinic acetylcholine receptors. In: Journal of Biological Chemistry, 295 (20). pp. 7096-7112.

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Official URL: https://doi.org/10.1074/jbc.RA119.012098

Abstract

Conopeptides are neurotoxic peptides in the venom of marine cone snails and have broad therapeutic potential for managing pain and other conditions. Here, we identified the single-disulfide peptides Czon1107 and Cca1669 from the venoms of Conus zonatus and Conus caracteristicus, respectively. We observed that Czon1107 strongly inhibits the human α3β4 (IC50 15.7 + 3.0 μM) and α7 (IC50 77.1 + 0.05 μM) nicotinic acetylcholine receptor (nAChR) subtypes, but the activity of Cca1669 remains to be identified. Czon1107 acted at a site distinct from the orthosteric receptor site. Solution NMR experiments revealed that Czon1107 exists in equilibrium between conformational states that are the result of a key Ser4–Pro5 cis-trans isomerization. Moreover, we found that the X-Pro amide bonds in the inter-cysteine loop are rigidly constrained to cis conformations. Structure-activity experiments of Czon1107 and its variants at positions P5 and P7 revealed that the conformation around the X-Pro bonds (cis-trans) plays an important role in receptor subtype selectivity. The cis conformation at the Cys6–Pro7 peptide bond was essential for α3β4 nAChR subtype allosteric selectivity. In summary, we have identified a unique single-disulfide conopeptide with a noncompetitive, potentially allosteric inhibitory mechanism at the nAChRs. The small size and rigidity of the Czon1107 peptide could provide a scaffold for rational drug design strategies for allosteric nAChR modulation. This new paradigm in the “conotoxinomic” structure-function space provides an impetus to screen venom from other Conus species for similar, short bioactive peptides that allosterically modulate ligand-gated receptor function. © 2020 Mohan et al. Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc.

Item Type: Journal Article
Publication: Journal of Biological Chemistry
Publisher: American Society for Biochemistry and Molecular Biology Inc.
Additional Information: The copyright to this article belongs to the authors
Keywords: Amides; Amino acids; Isomerization; Nuclear magnetic resonance spectroscopy; Rigidity; Scaffolds; Sulfur compounds; Tobacco, Cis-trans Isomerization; Conformational state; Inhibitory mechanism; Nicotinic acetylcholine receptors; Nicotinic acetylcholine receptors (nAChR); Rational drug designs; Structure functions; Therapeutic potentials, Peptides, amide; bungarotoxin receptor; cysteine; nicotinic acetylcholine receptor alpha3beta4; nicotinic receptor; peptide; proline; single disulfide conopeptide; unclassified drug, allosterism; amino terminal sequence; Article; carboxy terminal sequence; conformation; controlled study; Conus caracteristicus; Conus zonatus; high performance liquid chromatography; isomerization; nonhuman; nuclear magnetic resonance; nuclear magnetic resonance spectroscopy; peptide synthesis; priority journal; sequence alignment; snail; structure activity relation
Department/Centre: Division of Biological Sciences > Molecular Biophysics Unit
Date Deposited: 05 Aug 2021 11:37
Last Modified: 05 Aug 2021 11:37
URI: http://eprints.iisc.ac.in/id/eprint/65597

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