ALPHA-CONOTOXIN EI, A NEW NICOTINIC ACETYLCHOLINE-RECEPTOR ANTAGONIST WITH NOVEL SELECTIVITY
ALPHA-CONOTOXIN EI, A NEW NICOTINIC ACETYLCHOLINE-RECEPTOR ANTAGONIST WITH NOVEL SELECTIVITY
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DOI：
10.1021/bi00044a030
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发表时间：
1995-11-07
期刊：
影响因子：
2.9
通讯作者：
MCINTOSH, JM
中科院分区：
文献类型：
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作者：
MARTINEZ, JS;OLIVERA, BM;MCINTOSH, JM
我们报道了一种新型烟碱乙酰胆碱受体（nAChR）配体的分离和表征。这种毒素是一种由18个氨基酸组成的肽，是首次报道的来自大西洋捕鱼Conus的α - concontoxin。该肽是从圆锥蛇毒中纯化出来的，称为α -圆锥蛇毒EI。该序列与先前分离的α -conotoxins的序列不同。我们证明，这种结构分歧具有功能后果。在鱼雷nAChRs中，α - concontoxin EI选择性地结合α / δ亚基界面附近的激动剂位点，而α - concontoxin MI选择性地靶向α / γ激动剂结合位点。在哺乳动物nAChRs中，α - concontoxin EI对α / δ和α / γ亚基界面都有很高的亲和力（对α / δ位点有一定的偏好），而α - concontoxin MI对α / γ配体结合位点有很高的选择性。该肽的序列为：arg - asp - hypy - cys - cys - tyr - his - pro - thr - cys - asn - met - ser - asn - pro - gln - ile - cys - nh2，在Cys4-Cys10和Cys5-Cys18之间有二硫桥接，类似于先前描述的α -conotoxins。该序列已被全化学合成证实。因此，α - concontoxin EI具有独特的结构和功能，是一种新的表征nachr的工具。
We report the isolation and characterization of a novel nicotinic acetylcholine receptor (nAChR) ligand. The toxin is an 18 amino acid peptide and is the first reported alpha-conotoxin from an Atlantic fish-hunting Conus. The peptide was purified from the venom of Conus ermineus and is called alpha-conotoxin EI. The sequence diverges from that of previously isolated alpha-conotoxins. We demonstrate that this structural divergence has functional consequences. In Torpedo nAChRs, alpha-conotoxin EI selectively binds the agonist site near the alpha/delta subunit interface in contrast to alpha-conotoxin MI which selectively targets the alpha/gamma agonist binding site. In mammalian nAChRs alpha-conotoxin EI shows high affinity for both the alpha/delta and alpha/gamma subunit interfaces (with some preference for the alpha/delta site), whereas alpha-conotoxin MI is highly selective for the alpha/gamma ligand binding site. The sequence of the peptide is: Arg-Asp-Hyp-Cys-Cys-Tyr-His-Pro-Thr-Cys-Asn-Met-Ser-Asn-Pro-Gln-Ile-Cys-NH2, with disulfide bridging between Cys4-Cys10 and Cys5-Cys18, analogous to those of previously described alpha-conotoxins. This sequence has been verified by total chemical synthesis. Thus, alpha-conotoxin EI is a newly-available tool with unique structure and function for characterization of nAChRs.