Molecular dynamics simulation links conformation of a pore-flanking region to hyperekplexia-related dysfunction of the inhibitory glycine receptor
Molecular dynamics simulation links conformation of a pore-flanking region to hyperekplexia-related dysfunction of the inhibitory glycine receptor
复制标题
DOI：
10.1016/j.chembiol.2004.07.008
复制
发表时间：
2004-10-01
影响因子：
--
通讯作者：
Becker, CM
中科院分区：
文献类型：
--
作者：
Breitinger, HG;Lanig, H;Becker, CM
抑制性甘氨酸受体介导哺乳动物脊髓和脑干的快速突触抑制。先前鉴定的位于GlyR α 1亚基的细胞内TM 1 -2环内的高丛突变GLRA I（P250 T）导致改变的受体活化和脱敏。在这里，离子通道功能的α 1（250）突变体的基本步骤被解决，并显示与亲水性和残基α 1（250）的摩尔体积。使用激光脉冲光解的单通道记录和快速激活动力学研究表明，电导降低，但类似的α 1（P250 T）突变体通道的开放概率。代表细胞内TM 1 -2结构域的螺旋-转角-螺旋基序的分子动力学模拟揭示了骨架构象的改变，表明这些突变体的灵活性增加，从而改变了通道功能的基本步骤。因此，TM 1 -2环的结构是离子通道电导和受体脱敏的关键决定因素。
Inhibitory glycine receptors mediate rapid synaptic inhibition in mammalian spinal cord and brainstem. The previously identified hyperekplexia mutation GLRA I(P250T), located within the intracellular TM1-2 loop of the GlyR alpha1 subunit, results in altered receptor activation and desensitization. Here, elementary steps of ion channel function of alpha1(250) mutants were resolved and shown to correlate with hydropathy and molar volume of residue alpha1 (250). Single-channel recordings and rapid activation kinetic studies using laser pulse photolysis showed reduced conductance but similar open probability of alpha1 (P250T) mutant channels. Molecular dynamics simulation of a helix-turn-helix motif representing the intracellular TM1-2 domain revealed alterations in backbone conformation, indicating an increased flexibility in these mutants that paralleled changes in elementary steps of channel function. Thus, the architecture of the TM1-2 loop is a critical determinant of ion channel conductance and receptor desensitization.