Molecular Dynamics Simulations of GABA Binding to the GABA_C Receptor: The Role of Arg¹⁰⁴

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• 作者：Claudio Melis ; Sarah C.R. Lummis ; Carla Molteni
• 刊名：Biophysical Journal
• 出版年：2008
• 出版时间：1 November 2008
• 年：2008
• 卷：95
• 期：9
• 页码：4115-4123
• 全文大小：984 K

文摘

GABA is the major inhibitory neurotransmitter in the nervous system and acts at a variety of receptors including GABA_C receptors, which are a subclass of GABA_A receptors. Here we have used molecular dynamics simulations of GABA docked into the extracellular domain of the GABA_C 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 GABA_C 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.