A Gating Mechanism of the Serotonin 5-HT3 Receptor.
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.
Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland. Electronic address: shuguang.yuan@gmail.com.
Shuguang
S
Yuan
Laboratory of Biomodeling, Faculty of Chemistry & Biological and Chemical Research Centre, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland.
Slawomir
S
Filipek
Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland. Electronic address: horst.vogel@epfl.ch.
Horst
H
Vogel
D000818:Animals; D002713:Chlorine / Q000378:metabolism; D015640:Ion Channel Gating; D051379:Mice; D056004:Molecular Dynamics Simulation; D000072417:Protein Domains; D044406:Receptors, Serotonin, 5-HT3 / Q000737:chemistry* / Q000378:metabolism
D044406:Receptors, Serotonin, 5-HT3; D002713:Chlorine