Yuan Shuguang, Filipek Slawomir, Vogel Horst
Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
Laboratory of Biomodeling, Faculty of Chemistry & Biological and Chemical Research Centre, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland.
Structure. 2016 May 3;24(5):816-825. doi: 10.1016/j.str.2016.03.019. Epub 2016 Apr 21.
Our recently solved high-resolution structure of the serotonin 5-HT3 receptor (5-HT3R) delivered the first detailed structural insights for a mammalian pentameric ligand-gated ion channel. Based on this structure, we here performed a total of 2.8-μs all-atom molecular dynamics simulations to unravel at atomic detail how neurotransmitter binding on the extracellular domain induces sequential conformational transitions in the receptor, opening an ion channel and translating a chemical signal into electrical impulses across the membrane. We found that serotonin binding first induces distinct conformational fluctuations at the side chain of W156 in the highly conserved ligand-binding cage, followed by tilting-twisting movements of the extracellular domain which couple to the transmembrane TM2 helices, opening the hydrophobic gate at L260 and forming a continuous transmembrane water pathway. The structural transitions in the receptor's transmembrane part finally couple to the intracellular MA helix bundle, opening lateral ports for ion passage.
我们最近解析的血清素5-HT3受体（5-HT3R）的高分辨率结构，为哺乳动物五聚体配体门控离子通道提供了首个详细的结构见解。基于此结构，我们在此进行了总共2.8微秒的全原子分子动力学模拟，以在原子细节上揭示神经递质与细胞外结构域的结合如何在受体中诱导连续的构象转变，打开离子通道并将化学信号转化为跨膜的电脉冲。我们发现，血清素结合首先在高度保守的配体结合笼中W156的侧链处诱导明显的构象波动，随后是细胞外结构域的倾斜-扭转运动，该运动与跨膜TM2螺旋耦合，打开L260处的疏水门并形成连续的跨膜水通道。受体跨膜部分的结构转变最终与细胞内MA螺旋束耦合，打开离子通过的侧向通道。
