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Isolation and characterization of α-conotoxin LsIA with potent activity at nicotinic acetylcholine receptors
Inserra, M.C.; Kompella, S.N.; Vetter, I.; Brust, A.; Daly, N.L.; Cuny, H.; Craik, D.J.; Alewood, P.F.; Adams, D.J.; Lewis, R.J. (2013). Isolation and characterization of α-conotoxin LsIA with potent activity at nicotinic acetylcholine receptors. Biochem. Pharmacol. 86(6): 791-799. https://dx.doi.org/10.1016/j.bcp.2013.07.016
In: Biochemical Pharmacology. Pergamon Press: London; New York. ISSN 0006-2952; e-ISSN 1873-2968, more
Peer reviewed article  

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Keyword
    Marine/Coastal
Author keywords
    Conus limpusi a-Conotoxin Nicotinic acetylcholine receptor NMR structure FLIPR Electrophysiology

Authors  Top 
  • Inserra, M.C.
  • Kompella, S.N.
  • Vetter, I., more
  • Brust, A.
  • Daly, N.L.
  • Cuny, H.
  • Craik, D.J.
  • Alewood, P.F.
  • Adams, D.J.
  • Lewis, R.J.

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.

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