Dopamine transporter comparative molecular modeling and binding site prediction using the LeuTAa leucine transporter as a template
Dopamine transporter comparative molecular modeling and binding site prediction using the LeuTAa leucine transporter as a template
复制标题
DOI：
10.1002/prot.21598
复制
发表时间：
2008-02-15
影响因子：
2.9
通讯作者：
Surratt, Christopher K.
中科院分区：
文献类型：
--
作者：
Indarte, Martin;Madura, Jeffry D.;Surratt, Christopher K.
药理学和行为学研究表明，多巴胺转运体（DAT）蛋白与可卡因和安非他明的结合是引发与这些药物相关的欣快和成瘾的主要原因。由于缺乏DAT或神经递质钠同向转运体（NSS）家族的任何其他成员的X射线晶体结构，阻碍了在原子水平上对精神兴奋剂识别的理解，结构信息主要来自诱变和生物物理研究。最近发表的晶体结构的细菌亮氨酸转运蛋白LeuT（Aa），一个远亲NSS家族同系物，首次提供了一个模板的NSS蛋白质的三维比较建模。使用分子操作环境程序莫伊2005.06的能力结合其他比较建模服务器的一种新的计算建模方法生成了LeuT（Aa）-定向DAT模型。可能的多巴胺和安非他明结合位点内的DAT模型使用多种对接方法进行了鉴定。底物配体（多巴胺和安非他明）的结合位点基本上与底物亮氨酸的LeuTAa晶体结构的类似区域重叠。对接预测涉及DAT侧链已知是高亲和力配体结合的关键，并建议在阐明离散的底物和抑制剂结合位点的新的诱变目标。DAT模型可以指导DAT配体的定量构效关系研究，并合理设计新的DAT结合治疗药物。
Pharmacological and behavioral studies indicate that binding of cocaine and the amphetamines by the dopamine transporter (DAT) protein is principally responsible for initiating the euphoria and addiction associated with these drugs. The lack of an X-ray crystal structure for the DAT or any other member of the neurotransmitter:sodium symporter (NSS) family has hindered understanding of psychostimulant recognition at the atomic level, structural information has been obtained largely from mutagenesis and biophysical studies. The recent publication of a crystal structure for the bacterial leucine transporter LeuT(Aa), a distantly related NSS family homolog, provides for the first time a template for three-dimensional comparative modeling of NSS proteins. A novel computational modeling approach using the capabilities of the Molecular Operating Environment program MOE 2005.06 in conjunction with other comparative modeling servers generated the LeuT(Aa)-directed DAT model. Probable dopamine and amphetamine binding sites were identified within the DAT model using multiple docking approaches. Binding sites for the substrate ligands (dopamine and amphetamine) overlapped substantially with the analogous region of the LeuTAa crystal structure for the substrate leucine. The docking predictions implicated DAT side chains known to be critical for high affinity ligand binding and suggest novel mutagenesis targets in elucidating discrete substrate and inhibitor binding sites. The DAT model may guide DAT ligand QSAR studies, and rational design of novel DAT-binding therapeutics.