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A Gating Mechanism of the Serotonin 5-HT3 Receptor

已有 2156 次阅读 2016-4-22 15:55 |系统分类:科研笔记

Full Text

DOI:10.1016/j.str.2016.03.019


Highlights

  • Rotamer change of W156 in the highly conserved aromatic cage

  • Tilting-twisting movements captured at the extracellular domain

  • Rotamer change of L260 lead to formation of a continuous water pathway

  • Chlorine ions penetrate into the intracellular vestibule

Summary

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.





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