Homology modeling and dynamics of the extracellular domain of rat and human neuronal nicotinic acetylcholine receptor subtypes α4β2 and α7
Homology modeling and dynamics of the extracellular domain of rat and human neuronal nicotinic acetylcholine receptor subtypes α4β2 and α7
复制标题
DOI：
10.1007/s00894-008-0340-x
复制
发表时间：
2008-10-01
影响因子：
2.2
通讯作者：
Scapozza, Leonardo
中科院分区：
文献类型：
--
作者：
Bisson, William H.;Westera, Gerrit;Scapozza, Leonardo
近年来，已经清楚的是，神经元烟碱乙酰胆碱受体（nAChR）是治疗多种疾病的有效靶点，包括阿尔茨海默病、焦虑和尼古丁成瘾。与大多数膜蛋白一样，nAChR的三维（3D）结构信息仅限于电子显微镜的数据，其分辨率使得基于结构的设计方法难以应用于开发特定配体。基于AChBP的高分辨率晶体结构，建立了神经元大鼠和人nAChR亚型α 4 β 2和α 7（脑中最丰富的亚型）的胞外结构域的同源模型，并用分子动力学（MD）评估了其稳定性。构建的所有模型均显示出随时间推移的构象稳定性，证实了起始3D模型的质量。对大鼠和人类α 4 β 2和α 7烟碱模型进行的亲脂性和静电势研究与AChBP进行了比较，揭示了疏水芳香口袋的重要性和α亚基Trp-AChBP-Trp 143-的同系物-对配体结合的关键作用。所提出的模型提供了一个有价值的框架，以结构为基础的设计，旨在提高治疗和诊断应用的特定α 4 β 2 nAChR亚型配体。
In recent years, it has become clear that the neuronal nicotinic acetylcholine receptor (nAChR) is a valid target in the treatment of a variety of diseases, including Alzheimer's disease, anxiety, and nicotine addiction. As with most membrane proteins, information on the three-dimensional (3D) structure of nAChR is limited to data from electron microscopy, at a resolution that makes the application of structure-based design approaches to develop specific ligands difficult. Based on a high-resolution crystal structure of AChBP, homology models of the extracellular domain of the neuronal rat and human nAChR subtypes alpha 4 beta 2 and alpha 7 (the subtypes most abundant in brain) were built, and their stability assessed with molecular dynamics (MD). All models built showed conformational stability over time, confirming the quality of the starting 3D model. Lipophilicity and electrostatic potential studies performed on the rat and human alpha 4 beta 2 and alpha 7 nicotinic models were compared to AChBP, revealing the importance of the hydrophobic aromatic pocket and the critical role of the alpha-subunit Trp-the homolog of AChBP-Trp 143-for ligand binding. The models presented provide a valuable framework for the structure-based design of specific alpha 4 beta 2 nAChR subtype ligands aimed at improving therapeutic and diagnostic applications.