首页> 外文期刊>Biochemistry >Residues in the #epsilon# Subunit of the Nicotinic Acetylcholine Receptor Interact To Confer Selectivity of Walgerin-1 for the #alpha#-#epsilon# Subunit Interface Site
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Residues in the #epsilon# Subunit of the Nicotinic Acetylcholine Receptor Interact To Confer Selectivity of Walgerin-1 for the #alpha#-#epsilon# Subunit Interface Site

机译:烟碱乙酰胆碱受体的#epsilon#亚基中的残基相互作用以赋予Walgerin-1对#alpha#-#epsilon#亚基界面位点的选择性

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摘要

Walgerin-1 (Wtx-1) is a 22-amino acid peptide that competitively antagonizes muscle nicotinic acetylcholine receptors (nAChRs). Previous work demonstrated that Wtx-1 binds to mouse nAChRs with higher affinity than receptors from rats of humans, and distinghished residues in #alpha# and #epsilon# subunits that govern the species selectivity. These studies also showed that Wtx-1 binds selectively to the #alpha#-#epsilon# binding site with signifiantly higher affinity than to the #alpha#-#delta# binding site.Here we identify residues at equivalent positions in the #epsilon#, #gamma#, and #delta# sunbunits that govern Wtx-1 selectivity for one of the two binding sites on the nAChR pentamer. Using a series of chimeric and point mutant subunits, we show that residues Gly-57, Asp-59, Tyr-111, Tyr-115, and Asp-173 of the #epsilon# subunit account predominantly for the 3700-fold higher affinity of the #alpha#-#epsilon# site relative to that of the #alpha#-#gamma# site. Similarly, we find that residues Lys-34, Gly-57, Asp-59, and Asp-173 account predominantly for the higher affinity of the #alpha#-#epsilon# site relative to that of the #alpha#-#delta# site. Analysis of combinations of point mutations reveals that Asp-173 in the #epsilon# subunit is required together with the remaining deterinants in the #epsilon# subunit to achieve Wtx-1 selectivity. In particular, Lys-34 interacts with Asp-173 to confer higher affinity, resulting in a #DELTA##DELTA#G_INT of -2.3 kcal/mol in the #epsilon# subunit and a #DELTA##DELTA#G_INT of - 1.3 kcal/mol in the #delta# subunit. Asp-173 is part of a nonhomologus insertion not found in the acetylcholine binding protein structure. The key role of this insertion in Wtx-1 selectivity indicates that it is proximal to the ligand binding site. We use the binding and interaction energies for Wtx-1 to generate structural models of the #alpha#-#epsilon#, #alpha#-#gamma#, and #alpha#-#delta# binding sites containing the nonhomologous insertion.
机译:Walgerin-1(Wtx-1)是22个氨基酸的肽,可竞争性拮抗肌肉的烟碱乙酰胆碱受体(nAChRs)。先前的研究表明,Wtx-1与小鼠nAChRs的亲和力高于人类大鼠的受体,并区分了控制物种选择性的#alpha#和#epsilon#亚基中的残基。这些研究还表明,Wtx-1与#alpha#-#epsilon#结合位点选择性结合的亲和力明显高于与#alpha#-#delta#结合位点的亲和力。在这里,我们确定了#epsilon#中相同位置的残基,#gamma#和#delta#sunbunits控制Wtx-1对nAChR五聚体上两个结合位点之一的选择性。使用一系列嵌合和点突变亚基,我们显示了#epsilon#亚基的残基Gly-57,Asp-59,Tyr-111,Tyr-115和Asp-173占3700倍高的亲和力#alpha#-#epsilon#网站相对于#alpha#-#gamma#网站的位置。同样,我们发现残基Lys-34,Gly-57,Asp-59和Asp-173相对于#alpha#-#epsilon#位点相对于#alpha#-#delta#位点具有更高的亲和力现场。对点突变组合的分析表明,需要#epsilon#亚基中的Asp-173以及#epsilon#亚基中的其余决定剂才能实现Wtx-1选择性。具体而言,Lys-34与Asp-173相互作用以赋予更高的亲和力,从而导致#epsilon#亚基中的#DELTA ## DELTA#G_INT为-2.3 kcal / mol,而#DELTA ## DELTA#G_INT为-1.3。 #delta#亚基中的kcal / mol。 Asp-173是在乙酰胆碱结合蛋白结构中找不到的非同源插入的一部分。这种插入在Wtx-1选择性中的关键作用表明它靠近配体结合位点。我们使用Wtx-1的结合能和相互作用能来生成包含非同源插入的#alpha#-#epsilon#,#alpha#-#gamma#和#alpha#-#delta#结合位点的结构模型。

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