Molecular dynamics of leucine and dopamine transporter proteins in a model cell membrane lipid bilayer.
Molecular dynamics of leucine and dopamine transporter proteins in a model cell membrane lipid bilayer.
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DOI：
10.1002/prot.22601
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发表时间：
2010-03
期刊：
影响因子：
2.9
通讯作者：
Madura JD
中科院分区：
文献类型：
--
作者：
Gedeon PC;Indarte M;Surratt CK;Madura JD
多巴胺转运体（DAT）通过易化扩散发挥作用，利用向内的钠离子梯度将多巴胺从细胞外突触间隙转运至神经元内部。DAT与中枢神经系统疾病相关，比如帕金森病和注意缺陷多动障碍，并且是滥用的精神兴奋剂可卡因和苯丙胺的主要作用位点。一种DAT同系物——细菌亮氨酸转运体LeuT的结晶，提供了第一个可靠的三维DAT模板。在此，LeuT晶体结构和DAT分子模型已分别与它们各自的底物亮氨酸和多巴胺相结合，在脂质双层分子动力学模拟中，用于追踪底物沿蛋白质的底物/离子渗透途径的运动。具体而言，作为底物存在的函数，对构成“外部门”的残基对的运动进行了追踪。无论是否存在底物，与LeuT相比，跨膜（TM）1精氨酸 - TM10天冬氨酸支撑结构在DAT中更不易形成。对于LeuT而非DAT，底物的加入增加了形成TM1 - 10桥的可能性。此外，在存在底物的情况下，第四个细胞外环EL - 4的运动在DAT中更为明显，EL - 4有一定程度的解旋。LeuT和DAT分子动力学模拟之间的总体相似性表明，LeuT是指导DAT结构 - 功能预测的合理模型。然而，存在足够显著的差异，从而能够获得关于DAT的独特见解，这可能包括可卡因、哌甲酯（利他林，美国国家药物滥用研究所药物供应中心，罗克维尔，马里兰州）和其他DAT阻滞剂尽管能够进入主要底物结合口袋，但为何不被识别为底物。
The dopamine transporter (DAT) operates via facilitated diffusion, harnessing an inward Na+ gradient to drive dopamine from the extracellular synaptic cleft to the neuron interior. The DAT is relevant to central nervous system disorders such as Parkinson disease and attention-deficit hyperactivity disorder and is the primary site of action for the abused psychostimulants cocaine and amphetamines. Crystallization of a DAT homolog, the bacterial leucine transporter LeuT, provided the first reliable 3-D DAT template. Here, the LeuT crystal structure and the DAT molecular model have been combined with their respective substrates, leucine and dopamine, in lipid bilayer molecular dynamics simulations toward tracking substrate movement along the protein’s substrate/ion permeation pathway. Specifically, movement of residue pairs that comprise the “external gate” was followed as a function of substrate presence. The transmembrane (TM) 1 arginine-TM 10 aspartate strut formed less readily in DAT compared with LeuT, with or without substrate present. For LeuT but not DAT, the addition of substrate enhanced the chances of forming the TM 1–10 bridge. Also, movement of the fourth extracellular loop EL-4 in the presence of substrate was more pronounced for DAT, the EL-4 unwinding to a degree. The overall similarity between the LeuT and DAT molecular dynamics simulations indicated that LeuT was a legitimate model to guide DAT structure-function predictions. There were, nevertheless, differences significant enough to allow for DAT-unique insights, which may include how cocaine, methylphenidate (Ritalin, NIDA Drug Supply, Rockville, MD), and other DAT blockers are not recognized as substrates even though they can access the primary substrate binding pocket.
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影响因子：
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通讯作者：
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影响因子：
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