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首页> 美国卫生研究院文献>The Journal of Biological Chemistry >Conserved Water-mediated Hydrogen Bond Network between TM-I -II -VI and -VII in 7TM Receptor Activation
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Conserved Water-mediated Hydrogen Bond Network between TM-I -II -VI and -VII in 7TM Receptor Activation

机译：7TM受体激活中TM-1-II-VI和-VII之间的保守水介导氢键网络

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摘要

Five highly conserved polar residues connected by a number of structural water molecules together with two rotamer micro-switches, TrpVI:13 and TyrVII:20, constitute an extended hydrogen bond network between the intracellular segments of TM-I, -II, -VI, and -VII of 7TM receptors. Molecular dynamics simulations showed that, although the fewer water molecules in rhodopsin were relatively movable, the hydrogen bond network of the β2-adrenergic receptor was fully loaded with water molecules that were surprisingly immobilized between the two rotamer switches, both apparently being in their closed conformation. Manipulations of the rotamer state of TyrVII:20 and TrpVI:13 demonstrated that these residues served as gates for the water molecules at the intracellular and extracellular ends of the hydrogen bond network, respectively. TrpVI:13 at the bottom of the main ligand-binding pocket was shown to apparently function as a catching trap for water molecules. Mutational analysis of the β2-adrenergic receptor demonstrated that the highly conserved polar residues of the hydrogen bond network were all important for receptor signaling but served different functions, some dampening constitutive activity (AsnI:18, AspII:10, and AsnVII:13), whereas others (AsnVII:12 and AsnVII:16) located one helical turn apart and sharing a water molecule were shown to be essential for agonist-induced signaling. It is concluded that the conserved water hydrogen bond network of 7TM receptors constitutes an extended allosteric interface between the transmembrane segments being of crucial importance for receptor signaling and that part of the function of the rotamer micro-switches, TyrVII:20 and TrpVI:13, is to gate or trap the water molecules.
机译：由多个结构水分子与两个旋转微开关TrpVI：13和TyrVII：20连接的五个高度保守的极性残基构成了TM-1，-II，-VI，和-VII是7TM受体。分子动力学模拟表明，尽管视紫红质中的水分子相对可移动的较少，但β2-肾上腺素能受体的氢键网络中充满了出乎意料地固定在两个旋转异构体开关之间的水分子，两者显然处于闭合构型。 TyrVII：20和TrpVI：13的旋转异构体状态的操纵表明，这些残基分别充当氢键网络的细胞内和细胞外末端水分子的门。主要配体结合口袋底部的TrpVI：13显然起着捕集水分子的作用。对β2-肾上腺素能受体的突变分析表明，氢键网络的高度保守的极性残基对受体信号传导均很重要，但具有不同的功能，有一定的阻尼本构活性（AsnI：18，AspII：10和AsnVII：13），而其他分子（AsnVII：12和AsnVII：16）位于一个螺旋角并共享一个水分子，这对激动剂诱导的信号传导至关重要。结论是，保守的7TM受体水氢键网络构成跨膜段之间的扩展变构界面，这对于受体信号传导至关重要，旋转异构体微开关TyrVII：20和TrpVI：13的部分功能，用来控制或捕获水分子。

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