Molecular dynamics simulations of GABA binding to the GABAC receptor: the role of Arg104.
Molecular dynamics simulations of GABA binding to the GABAC receptor: the role of Arg104.
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DOI：
10.1529/biophysj.107.127589
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发表时间：
2008-11-01
影响因子：
3.4
通讯作者：
Molteni C
中科院分区：
文献类型：
--
作者：
Melis C;Lummis SC;Molteni C
GABA是神经系统中主要的抑制性神经递质，作用于多种受体，其中GABAC受体是GABAA受体的一个亚类。在这里，我们使用分子动力学模拟GABA停靠在GABAC受体的细胞外区域，以解释神经递质与结合位点残基的分子相互作用；特别是，我们探索了GABA与Arg104的相互作用。模拟结果表明，GABA的胺基与Tyr102和Tyr198形成阳离子-π相互作用，与Gln83、Glu220、Ser243和Ser168形成氢键，最显著的是与Arg104形成氢键。用Ala、Glu或Lys等实验破坏GABAC受体功能的氨基酸取代Arg104，重复模拟发现与GABA的结合模式更少且不同，或者GABA从结合口袋中快速退出。因此，模拟揭示了GABA在结合袋内的相互作用，并解释了实验数据，这些数据表明Arg104对受体的有效功能至关重要。
GABA is the major inhibitory neurotransmitter in the nervous system and acts at a variety of receptors including GABAC receptors, which are a subclass of GABAA receptors. Here we have used molecular dynamics simulations of GABA docked into the extracellular domain of the GABAC receptor to explain the molecular interactions of the neurotransmitter with the residues that contribute to the binding site; in particular, we have explored the interaction of GABA with Arg104. The simulations suggest that the amine group of GABA forms cation-π interactions with Tyr102 and Tyr198, and hydrogen-bonds with Gln83, Glu220, Ser243, and Ser168, and, most prominently, with Arg104. Substituting Arg104 with Ala, Glu, or Lys, which experimentally disrupt GABAC receptor function, and repeating the simulation revealed fewer and different bonding patterns with GABA, or the rapid exit of GABA from the binding pocket. The simulations therefore unveil interactions of GABA within the binding pocket, and explain experimental data, which indicate that Arg104 is critical for the efficient functioning of the receptor.
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影响因子：
11.4
作者：
Hansen, SB;Sulzenbacher, G;Bourne, Y
通讯作者：
Bourne, Y
影响因子：
3
作者：
SINGH, UC;KOLLMAN, PA
通讯作者：
KOLLMAN, PA
DOI：
10.1002/prot.10286
发表时间：
2003-02-15
期刊：
PROTEINS-STRUCTURE FUNCTION AND GENETICS
影响因子：
--
作者：
Lovell, SC;Davis, IW;Richardson, DC
通讯作者：
Richardson, DC
影响因子：
5.5
作者：
Krishek, BJ;Amato, A;Smart, TG
通讯作者：
Smart, TG
影响因子：
--
作者：
Lummis, SCR;Beene, DL;Dougherty, DA
通讯作者：
Dougherty, DA