Structures of Aplysia AChBP complexes with nicotinic agonists and antagonists reveal distinctive binding interfaces and conformations
Structures of Aplysia AChBP complexes with nicotinic agonists and antagonists reveal distinctive binding interfaces and conformations
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DOI：
10.1038/sj.emboj.7600828
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发表时间：
2005-10-19
期刊：
影响因子：
11.4
通讯作者：
Bourne, Y
中科院分区：
文献类型：
--
作者：
Hansen, SB;Sulzenbacher, G;Bourne, Y
在亚基界面处的配体结合后，烟碱乙酰胆碱受体的胞外结构域经历构象变化，并且激动剂结合变构地触发离子通道的开放。蜗牛的可溶性乙酰胆碱结合蛋白（AChBP）已被证明是受体配体结合域（LBD）的结构和功能替代物。然而，个别AChBP物种显示不同的亲和力烟碱配体。AChBP的晶体结构，从AChBP在载脂蛋白形式揭示了一个更开放的循环C和独特的位置为其他表面环，与以前的结构相比。分析AChBP与烟碱配体的复合物表明，环C，这并不显着改变构象的拮抗剂，methylylycaconitine结合后，进一步打开，以适应肽拮抗剂，α-芋螺毒素ImI，但周围的激动剂洛贝林和epibatidine包裹。该结构还揭示了两种拮抗剂在激动剂的结合位点之外的扩展和非重叠的相互作用表面。这套全面的结构反映了一个动态的模板描绘进一步的构象变化的LBD的烟碱受体。
Upon ligand binding at the subunit interfaces, the extracellular domain of the nicotinic acetylcholine receptor undergoes conformational changes, and agonist binding allosterically triggers opening of the ion channel. The soluble acetylcholine-binding protein (AChBP) from snail has been shown to be a structural and functional surrogate of the ligand-binding domain (LBD) of the receptor. Yet, individual AChBP species display disparate affinities for nicotinic ligands. The crystal structure of AChBP from Aplysia californica in the apo form reveals a more open loop C and distinctive positions for other surface loops, compared with previous structures. Analysis of Aplysia AChBP complexes with nicotinic ligands shows that loop C, which does not significantly change conformation upon binding of the antagonist, methyllycaconitine, further opens to accommodate the peptidic antagonist, alpha-conotoxin ImI, but wraps around the agonists lobeline and epibatidine. The structures also reveal extended and non-overlapping interaction surfaces for the two antagonists, outside the binding loci for agonists. This comprehensive set of structures reflects a dynamic template for delineating further conformational changes of the LBD of the nicotinic receptor.