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Alanine Scan of α-Conotoxin RegIIA Reveals a Selective α3β4 Nicotinic Acetylcholine Receptor Antagonist
被引:39
作者:
Kompella, Shiva N.
[1
]
Hung, Andrew
[1
]
Clark, Richard J.
[2
]
Mar, Frank
[3
]
Adams, David J.
[1
]
机构:
[1] RMIT Univ, Hlth Innovat Res Inst, Melbourne, Vic 3083, Australia
[2] Univ Queensland, Sch Biomed Sci, Brisbane, Qld 4072, Australia
[3] Florida Atlantic Univ, Dept Chem & Biochem, Boca Raton, FL 33431 USA
基金:
澳大利亚研究理事会;
关键词:
DIFFERENTIAL SENSITIVITY;
MOLECULAR-DYNAMICS;
AUTONOMIC GANGLIA;
CRYSTAL-STRUCTURE;
HOMOLOG ACHBP;
LUNG-CANCER;
ALPHA-9-ALPHA-10;
RAT;
SUBUNIT;
BINDING;
D O I:
10.1074/jbc.M114.605592
中图分类号:
Q5 [生物化学];
Q7 [分子生物学];
学科分类号:
071010 ;
081704 ;
摘要:
Activation of the alpha 3 beta 4 nicotinic acetylcholine receptor (nAChR) subtype has recently been implicated in the pathophysiology of various conditions, including development and progression of lung cancer and in nicotine addiction. As selective alpha 3 beta 4 nAChR antagonists, alpha-conotoxins are valuable tools to evaluate the functional roles of this receptor subtype. We previously reported the discovery of a new beta 4/7-conotoxin, RegIIA. RegIIA was isolated from Conus regius and inhibits acetylcholine (ACh)-evoked currents mediated by alpha 3 beta 4, alpha 3 beta 2, and alpha 7 nAChR subtypes. The current study used alanine scanning mutagenesis to understand the selectivity profile of RegIIA at the alpha 3 beta 4 nAChR subtype. [N11A] and [N12A] RegIIA analogs exhibited 3-fold more selectivity for the alpha 3 beta 4 than the alpha 3 beta 2 nAChR subtype. We also report synthesis of [N11A, N12A] RegIIA, a selective alpha 3 beta 4 nAChR antagonist (IC50 of 370 nM) that could potentially be used in the treatment of lung cancer and nicotine addiction. Molecular dynamics simulations of RegIIA and [N11A, N12A] RegIIA bound to alpha 3 beta 4 and alpha 3 beta 2 suggest that destabilization of toxin contacts with residues at the principal and complementary faces of alpha 3 beta 2 (alpha 3-Tyr(92), Ser(149), Tyr(189), Cys(192), and Tyr(196); beta 2-Trp(57), Arg(81), and Phe(119)) may form the molecular basis for the selectivity shift.
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页码:1039 / 1048
页数:10
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