Journal
STRUCTURE
Volume 24, Issue 5, Pages 816-825Publisher
CELL PRESS
DOI: 10.1016/j.str.2016.03.019
Keywords
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Funding
- National Center of Science, Poland [2011/03/B/NZ1/03204]
- Swiss National Science Foundation [31003A-133141]
- European Community [FP7-KBBE-2013-613879]
- internal funds of the EPFL
- Swiss National Science Foundation (SNF) [31003A_133141] Funding Source: Swiss National Science Foundation (SNF)
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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-mu s 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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