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

被引：53

作者：

Inserra, Marco C. ^{[1
]}

Kompella, Shiva N. ^{[2
]}

Vetter, Irina ^{[1
]}

Brust, Andreas ^{[1
]}

Daly, Norelle L. ^{[1
,3
]}

Cuny, Hartmut ^{[2
]}

Craik, David J. ^{[1
]}

Alewood, Paul F. ^{[1
]}

Adams, David J. ^{[2
]}

Lewis, Richard J. ^{[1
]}

机构：

[1] Univ Queensland, Inst Mol Biosci, Div Chem & Struct Biol, Brisbane, Qld 4072, Australia

[2] RMIT Univ, Hlth Innovat Res Inst, Melbourne, Vic 3083, Australia

[3] James Cook Univ, Sch Pharm & Mol Sci, Ctr Biodiscovery & Mol Dev Therapeut, Cairns 4878, Australia

来源：

BIOCHEMICAL PHARMACOLOGY | 2013年 / 86卷 / 06期

基金：

澳大利亚国家健康与医学研究理事会;

关键词：

Conus limpusi; alpha-Conotoxin; Nicotinic acetylcholine receptor; NMR structure; FLIPR; Electrophysiology; CRYSTAL-STRUCTURE; PEPTIDE ANTAGONIST; CONUS-GEOGRAPHUS; BINDING PROTEIN; BETA; PNIA; IDENTIFICATION; INACTIVATION; PHARMACOLOGY; LIGAND;

D O I：

10.1016/j.bcp.2013.07.016

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

A new alpha-conotoxin LsIA was isolated from the crude venom of Conus limpusi using assay-guided RP-HPLC fractionation. Synthetic LsIA was a potent antagonist of alpha 3 beta 2, alpha 3 alpha 5 beta 2 and alpha 7 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 alpha-helical structure and disordered N-terminal region. Potency reductions of up to 9-fold were observed for N-terminally truncated analogues of LsIA at alpha 7 and alpha 3 beta 2 nAChRs, whereas C-terminal carboxylation enhanced potency 3-fold at alpha 3 beta 2 nAChRs but reduced potency 3-fold at alpha 7 nAChRs. This study gives further insight into alpha-conotoxin pharmacology and the molecular basis of nAChR selectivity, highlighting the influence of N-terminal residues and C-terminal amidation on conotoxin pharmacology. (C) 2013 Published by Elsevier Inc.

引用

页码：791 / 799

页数：9

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