Crystal structure of nicotinic acetylcholine receptor homolog AChBP in complex with an α-conotoxin PnIA variant
Crystal structure of nicotinic acetylcholine receptor homolog AChBP in complex with an α-conotoxin PnIA variant
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DOI：
10.1038/nsmb951
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发表时间：
2005-07-01
影响因子：
16.8
通讯作者：
Smit, AB
中科院分区：
文献类型：
--
作者：
Celie, PHN;Kasheverov, IE;Smit, AB
芋螺毒素 (Ctx) 是来自锥螺毒液的一大类肽毒素，作用于广泛的离子通道和受体。 α-Ctx 亚组特异性且选择性地与烟碱乙酰胆碱受体 (nAChR) 亚型结合，后者是治疗多种神经系统疾病的靶点。在这里，我们以 2.4 埃的分辨率展示了 α-Ctx PnIA (A10L D14K) 的结构，α-Ctx PnIA (A10L D14K) 是 α(7)-nAChR 的有效阻断剂，与乙酰胆碱结合蛋白 (AChBP) 具有高亲和力，乙酰胆碱结合蛋白 (AChBP) 是 nAChR 超家族配体结合结构域的原型。 α-Ctx 深埋在配体结合位点内，并与相邻亚基两面上的残基相互作用。毒素本身不会改变构象，但会取代 AChBP 的 C 环并诱导刚体亚基运动。了解这些接触可以促进使用 Ctx 框架合理设计药物先导化合物，并可能产生具有增加的受体亚型选择性的化合物。
Conotoxins (Ctx) form a large family of peptide toxins from cone snail venoms that act on a broad spectrum of ion channels and receptors. The subgroup alpha-Ctx specifically and selectively binds to subtypes of nicotinic acetylcholine receptors (nAChRs), which are targets for treatment of several neurological disorders. Here we present the structure at a resolution of 2.4 angstrom of alpha-Ctx PnIA (A10L D14K), a potent blocker of the alpha(7)-nAChR, bound with high affinity to acetylcholine binding protein ( AChBP), the prototype for the ligand-binding domains of the nAChR superfamily. alpha-Ctx is buried deep within the ligand-binding site and interacts with residues on both faces of adjacent subunits. The toxin itself does not change conformation, but displaces the C loop of AChBP and induces a rigid-body subunit movement. Knowledge of these contacts could facilitate the rational design of drug leads using the Ctx framework and may lead to compounds with increased receptor subtype selectivity.