Flipped Phenyl Ring Orientations of Dopamine Binding with Human and Drosophila Dopamine Transporters: Remarkable Role of Three Nonconserved Residues.
Flipped Phenyl Ring Orientations of Dopamine Binding with Human and Drosophila Dopamine Transporters: Remarkable Role of Three Nonconserved Residues.
复制标题
多巴胺与人和果蝇多巴胺转运蛋白结合的翻转苯基环方向：三个非保守残基的显着作用。
DOI：
10.1021/acschemneuro.8b00030
复制
发表时间：
2018
影响因子：
5
通讯作者：
Zhan,Chang-Guo
中科院分区：
文献类型：
--
作者：
Yuan,Yaxia;Zhu,Jun;Zhan,Chang-Guo
Molecular modeling and molecular dynamics simulations were performed in the present study to examine the modes of dopamine binding with human andDrosophiladopamine transporters (hDAT and dDAT). The computational data revealed flipped binding orientations of dopamine in hDAT and dDAT due to the major differences in three key residues (S149, G153, and A423 of hDAT vs A117, D121, and S422 of dDAT) in the binding pocket. These three residues dictate the binding orientation of dopamine in the binding pocket, as the aromatic ring of dopamine tends to take an orientation with both the para- and meta-hydroxyl groups being close to polar residues and away from nonpolar residues of the protein. The flipped binding orientations of dopamine in hDAT and dDAT clearly demonstrate a generally valuable insight concerning how the species difference could drastically affect the protein–ligand binding modes, demonstrating that the species difference, which is a factor rarely considered in early drug design stage, must be accounted for throughout the ligand/drug design and discovery processes in general.
