Crystal structure of acetylcholine-binding protein from Bulinus truncatus reveals the conserved structural scaffold and sites of variation in nicotinic acetylcholine receptors
Crystal structure of acetylcholine-binding protein from Bulinus truncatus reveals the conserved structural scaffold and sites of variation in nicotinic acetylcholine receptors
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DOI：
10.1074/jbc.m414476200
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发表时间：
2005-07-15
影响因子：
4.8
通讯作者：
Sixma, TK
中科院分区：
文献类型：
--
作者：
Celie, PHN;Klaassen, RV;Sixma, TK
乙酰胆碱结合蛋白（acetylcholine-binding protein，AChBP）是一种新型的配体门控离子通道蛋白，其主要功能包括烟碱型乙酰胆碱、5-羟色胺（5-HT 3）、γ-氨基丁酸（GABA）、A型和C型受体以及甘氨酸受体。在这里，我们提出了一个远程同系物，AChBP从泡螺truncatus，这揭示了保守的结构支架和该受体家族的变化的网站的晶体结构。这些包括接近受体中跨膜界面的环的刚体运动和单体间接触的变化，其显著改变五聚体稳定性。两种乙酰胆碱结合蛋白的结构、药理学和突变分析显示，结合位点的3个氨基酸变化如何导致对烟碱配体的亲和力差异5-10倍。这些结构的比较将有助于提高配体门控离子通道受体的结构-功能研究，包括信号转导，同源建模和药物设计。
The crystal structure of acetylcholine-binding protein (AChBP) from the mollusk Lymnaea stagnalis is the established model for the ligand binding domains of the ligand-gated ion channel family, which includes nicotinic acetylcholine, 5-hydroxytryptamine (5-HT3), gamma-aminobutyric acid (GABA), types A and C, and glycine receptors. Here we present the crystal structure of a remote homolog, AChBP from Bulinus truncatus, which reveals both the conserved structural scaffold and the sites of variation in this receptor family. These include rigid body movements of loops that are close to the transmembrane interface in the receptors and changes in the intermonomer contacts, which alter the pentamer stability drastically. Structural, pharmacological and mutational analysis of both AChBPs shows how 3 amino acid changes in the binding site contribute to a 5-10-fold difference in affinity for nicotinic ligands. Comparison of these structures will be valuable for improving structure-function studies of ligand-gated ion channel receptors, including signal transduction, homology modeling, and drug design.