Isolation and characterization of α-conotoxin LsIA with potent activity at nicotinic acetylcholine receptors
RIS ID
105235
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.
Publication Details
Inserra, M. C., Kompella, S. N., Vetter, I., Brust, A., Daly, N. L., Cuny, H., Craik, D., Alewood, P. F., Adams, D. J. & Lewis, R. J. (2013). Isolation and characterization of α-conotoxin LsIA with potent activity at nicotinic acetylcholine receptors. Biochemical Pharmacology, 86 (6), 791-799.