From crystal structure of α-conotoxin GIC in complex with Ac-AChBP to molecular determinants of its high selectivity for α3β2 nAChR.
From crystal structure of α-conotoxin GIC in complex with Ac-AChBP to molecular determinants of its high selectivity for α3β2 nAChR.
复制标题
从 α-芋螺毒素 GIC 与 Ac-AChBP 复合物的晶体结构到其对 α3β2 nAChR 高选择性的分子决定因素。
DOI：
10.1038/srep22349
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发表时间：
2016-03-01
影响因子：
4.6
通讯作者：
Luo S
中科院分区：
文献类型：
--
作者：
Lin B;Xu M;Zhu X;Wu Y;Liu X;Zhangsun D;Hu Y;Xiang SH;Kasheverov IE;Tsetlin VI;Wang X;Luo S
乙酰胆碱结合蛋白（Acetylcholine binding proteins，AChBPs）是烟碱型乙酰胆碱受体（nAChRs）配体结合域的独特空间同源物，它们复制了nAChRs的某些药理学特性。与α-芋螺毒素复合的A β hBP的X射线晶体结构为α-芋螺毒素与不同nAChR亚型的相互作用提供了重要的见解。虽然已经做出了相当大的努力来理解为什么α-芋螺毒素GIC对α3β2 nAChR具有强选择性，但这个问题尚未得到解决。本文报道了α-芋螺毒素GIC与Ac-AChBP复合物（Ac-AChBP）的结构，其分辨率为2.1 nm。基于这种共晶结构，结合分子对接数据，我们提出了GIC的关键残基，这些残基决定了其对人α3β2与α3β4 nAChRs的高亲和力和选择性。这些建议通过放射性配体和电生理学实验进行了检查，证实了检测到的GIC与Ac-AChBP和α3β2 nAChR亚型相互作用的接触的功能作用。虽然GIC元件负责其与Ac-AChBP和α3β2 nAChR的高亲和力结合被确定，但我们的研究也显示了计算机建模在将AChBP复合物的X射线结构数据扩展到所有nAChR亚型方面的局限性。
Acetylcholine binding proteins (AChBPs) are unique spatial homologs of the ligand-binding domains of nicotinic acetylcholine receptors (nAChRs), and they reproduce some pharmacological properties of nAChRs. X-ray crystal structures of AСhBP in complex with α-conotoxins provide important insights into the interactions of α-conotoxins with distinct nAChR subtypes. Although considerable efforts have been made to understand why α-conotoxin GIC is strongly selective for α3β2 nAChR, this question has not yet been solved. Here we present the structure of α-conotoxin GIC in complex with Aplysia californica AChBP (Ac-AChBP) at a resolution of 2.1 Å. Based on this co-crystal structure complemented with molecular docking data, we suggest the key residues of GIC in determining its high affinity and selectivity for human α3β2 vs α3β4 nAChRs. These suggestions were checked by radioligand and electrophysiology experiments, which confirmed the functional role of detected contacts for GIC interactions with Ac-AChBP and α3β2 nAChR subtypes. While GIC elements responsible for its high affinity binding with Ac-AChBP and α3β2 nAChR were identified, our study also showed the limitations of computer modelling in extending the data from the X-ray structures of the AChBP complexes to all nAChR subtypes.