High Selectivity of an α-Conotoxin LvIA Analogue for α3β2 Nicotinic Acetylcholine Receptors Is Mediated by β2 Functionally Important Residues,Journal of Medicinal Chemistry

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High Selectivity of an α-Conotoxin LvIA Analogue for α3β2 Nicotinic Acetylcholine Receptors Is Mediated by β2 Functionally Important Residues
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-11-16 , DOI: 10.1021/acs.jmedchem.0c00975
Xiaopeng Zhu _{1,

2} , Si Pan ₃ , Manyu Xu ₃ , Lu Zhang ₂ , Jinfang Yu ₃ , Jinpeng Yu ₁ , Yong Wu ₁ , Yingxu Fan ₄ , Haonan Li ₂ , Igor E. Kasheverov _{5,

6} , Denis S. Kudryavtsev ₅ , Victor I. Tsetlin _{5,

7} , Yi Xue ₄ , Dongting Zhangsun _{1,

2} , Xinquan Wang ₃ , Sulan Luo _{1,

2}

Affiliation

The α3β2 and α3β4 nicotinic acetylcholine receptors (nAChRs) are widely expressed in the central and peripheral nervous systems, playing critical roles in various physiological processes and in such pathologies as addiction to nicotine and other drugs of abuse. α-Conotoxin LvIA, which we previously isolated from Conus lividus, modestly discriminates α3β2 and α3β4 rat nAChRs exhibiting a ∼17-fold tighter binding to the former. Here, alanine scanning resulted in two more selective analogues [N9A]LvIA and [D11A]LvIA, the former having a >2000-fold higher selectivity for α3β2. The determined crystal structures of [N9A]LvIA and [D11A]LvIA bound to the acetylcholine-binding protein (AChBP) were followed by homologous modeling of the complexes with the α3β2 and α3β4 nAChRs and by receptor mutagenesis, which revealed Phe106, Ser108, Ser113, and Ser168 residues in the β2 subunit as essential for LvIA binding. These results may be useful for the design of novel compounds of therapeutic potential targeting α3β2 nAChRs.

中文翻译：

β2功能重要的残基介导α-芋螺毒素LvIA类似物对α3β2烟碱乙酰胆碱受体的高选择性。

α3β2和α3β4烟碱乙酰胆碱受体（nAChRs）在中枢和周围神经系统中广泛表达，在各种生理过程中以及在对尼古丁和其他滥用药物成瘾的病理过程中发挥关键作用。α-芋螺毒素LvIA，我们先前从圆锥孢子虫中分离得到，适度区分α3β2和α3β4大鼠nAChRs表现出约17倍的紧密结合前者。在此，丙氨酸扫描产生了两个更多的选择性类似物[N9A] LvIA和[D11A] LvIA，前者对α3β2的选择性高> 2000倍。确定与乙酰胆碱结合蛋白（AChBP）结合的[N9A] LvIA和[D11A] LvIA的晶体结构，然后对与α3β2和α3β4nAChRs形成的复合物进行同源建模，并通过受体诱变，揭示出Phe106，Ser108，Ser113 β2亚基中的Ser168残基是LvIA结合所必需的。这些结果可能对设计具有治疗潜力的靶向α3β2nAChRs的新型化合物有用。

更新日期：2020-11-25

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