Isolation and characterization of alpha-conotoxin LsIA with potent activity at nicotinic acetylcholine receptors

Inserra, Marco C., Kompella, Shiva N., Vetter, Irina, Brust, Andreas, Daly, Norelle L., Cuny, Hartmut, Craik, David J., Alewood, Paul F., Adams, David J., and Lewis, Richard J. (2013) Isolation and characterization of alpha-conotoxin LsIA with potent activity at nicotinic acetylcholine receptors. Biochemical Pharmacology, 86 (6). pp. 791-799.

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Abstract

A new α-conotoxin LsIA was isolated from the crude venom of Conus limpusi using assay-guided RP-HPLC fractionation. Synthetic LsIA was a potent antagonist of α3β2, α3α5β2 and α7 nAChRs, with half-maximal inhibitory concentrations of 10, 31 and 10 nM, respectively. The structure of LsIA determined by NMR spectroscopy comprised a characteristic disulfide bond-stabilized α-helical structure and disordered N-terminal region. Potency reductions of up to 9-fold were observed for N-terminally truncated analogues of LsIA at α7 and α3β2 nAChRs, whereas C-terminal carboxylation enhanced potency 3-fold at α3β2 nAChRs but reduced potency 3-fold at α7 nAChRs. This study gives further insight into α-conotoxin pharmacology and the molecular basis of nAChR selectivity, highlighting the influence of N-terminal residues and C-terminal amidation on conotoxin pharmacology.

Item ID: 30191
Item Type: Article (Research - C1)
ISSN: 1873-2968
Keywords: Conus limpusi, alpha-Conotoxin, nicotinic acetylcholine receptor, NMR structure, FLIPR, electrophysiology
Funders: National Health and Medical Research Council (NHMRC), Australian Research Council (ARC)
Projects and Grants: NHMRC Program Grant (569927), ARC LIEF Grant
Date Deposited: 13 Nov 2013 05:27
FoR Codes: 03 CHEMICAL SCIENCES > 0304 Medicinal and Biomolecular Chemistry > 030401 Biologically Active Molecules @ 100%
SEO Codes: 97 EXPANDING KNOWLEDGE > 970103 Expanding Knowledge in the Chemical Sciences @ 100%
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