A cation-π binding interaction with a tyrosine in the binding site of the GABAC receptor
A cation-π binding interaction with a tyrosine in the binding site of the GABAC receptor
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DOI：
10.1016/j.chembiol.2005.06.012
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发表时间：
2005-09-01
影响因子：
--
通讯作者：
Dougherty, DA
中科院分区：
文献类型：
--
作者：
Lummis, SCR;Beene, DL;Dougherty, DA
GABA(C) (p)受体是Cys-loop神经递质受体超家族的成员，该家族包括烟碱乙酰胆碱（nACh）、5-HT3和甘氨酸受体。与该家族的其他成员一样，GABA(C)受体的激动剂结合位点富含芳香氨基酸，但当其他受体通过阳离子- π相互作用与色氨酸结合时，GABA(C)结合位点在对齐位置有酪氨酸。利用非自然氨基酸诱变技术在198位加入一系列酪氨酸衍生物，揭示了侧链的阳离子-pi结合能力与受体激活的EC50之间的明显相关性，从而证明了酪氨酸侧链与神经递质之间的阳离子-pi相互作用。四种同源受体之间的比较表明，阳离子- π结合能的变化反映了激动剂阳离子中心的性质。
GABA(C) (p) receptors are members of the Cys-loop superfamily of neurotransmitter receptors, which includes nicotinic acetylcholine (nACh), 5-HT3, and glycine receptors. As in other members of this family, the agonist binding site of GABA(C) receptors is rich in aromatic amino acids, but while other receptors bind agonist through a cation-pi interaction to a tryptophan, the GABA(C) binding site has tyrosine at the aligning positions. Incorporating a series of tyrosine derivatives at position 198 using unnatural amino acid mutagenesis reveals a clear correlation between the cation-pi binding ability of the side chain and EC50 for receptor activation, thus demonstrating a cation-pi interaction between a tyrosine side chain and a neurotransmitter. Comparisons among four homologous receptors show variations in cation-pi binding energies that reflect the nature of the cationic center of the agonist.