Conformational transitions of the serotonin 5-HT3 receptor

Lucie Polovinkin; Ghérici Hassaine; Jonathan Perot; Emmanuelle Neumann; Anders A Jensen; Solène N Lefebvre; Pierre-Jean Corringer; Jacques Neyton; Christophe Chipot; Francois Dehez; Guy Schoehn; Hugues Nury

doi:10.1038/s41586-018-0672-3

Conformational transitions of the serotonin 5-HT3 receptor

Lucie Polovinkin, Ghérici Hassaine, Jonathan Perot, Emmanuelle Neumann, Anders A Jensen, Solène N Lefebvre, Pierre-Jean Corringer, Jacques Neyton, Christophe Chipot, Francois Dehez, Guy Schoehn, Hugues Nury

59 Citations (Scopus)

Abstract

The serotonin 5-HT3 receptor is a pentameric ligand-gated ion channel (pLGIC). It belongs to a large family of receptors that function as allosteric signal transducers across the plasma membrane1,2; upon binding of neurotransmitter molecules to extracellular sites, the receptors undergo complex conformational transitions that result in transient opening of a pore permeable to ions. 5-HT3 receptors are therapeutic targets for emesis and nausea, irritable bowel syndrome and depression3. In spite of several reported pLGIC structures4-8, no clear unifying view has emerged on the conformational transitions involved in channel gating. Here we report four cryo-electron microscopy structures of the full-length mouse 5-HT3 receptor in complex with the anti-emetic drug tropisetron, with serotonin, and with serotonin and a positive allosteric modulator, at resolutions ranging from 3.2 Å to 4.5 Å. The tropisetron-bound structure resembles those obtained with an inhibitory nanobody5 or without ligand9. The other structures include an 'open' state and two ligand-bound states. We present computational insights into the dynamics of the structures, their pore hydration and free-energy profiles, and characterize movements at the gate level and cation accessibility in the pore. Together, these data deepen our understanding of the gating mechanism of pLGICs and capture ligand binding in unprecedented detail.

Original language	English
Journal	Nature
Volume	563
Issue number	7730
Pages (from-to)	275-279
Number of pages	5
ISSN	0028-0836
DOIs	https://doi.org/10.1038/s41586-018-0672-3
Publication status	Published - 8 Nov 2018

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title = "Conformational transitions of the serotonin 5-HT3 receptor",

abstract = "The serotonin 5-HT3 receptor is a pentameric ligand-gated ion channel (pLGIC). It belongs to a large family of receptors that function as allosteric signal transducers across the plasma membrane1,2; upon binding of neurotransmitter molecules to extracellular sites, the receptors undergo complex conformational transitions that result in transient opening of a pore permeable to ions. 5-HT3 receptors are therapeutic targets for emesis and nausea, irritable bowel syndrome and depression3. In spite of several reported pLGIC structures4-8, no clear unifying view has emerged on the conformational transitions involved in channel gating. Here we report four cryo-electron microscopy structures of the full-length mouse 5-HT3 receptor in complex with the anti-emetic drug tropisetron, with serotonin, and with serotonin and a positive allosteric modulator, at resolutions ranging from 3.2 {\AA} to 4.5 {\AA}. The tropisetron-bound structure resembles those obtained with an inhibitory nanobody5 or without ligand9. The other structures include an 'open' state and two ligand-bound states. We present computational insights into the dynamics of the structures, their pore hydration and free-energy profiles, and characterize movements at the gate level and cation accessibility in the pore. Together, these data deepen our understanding of the gating mechanism of pLGICs and capture ligand binding in unprecedented detail.",

author = "Lucie Polovinkin and Gh{\'e}rici Hassaine and Jonathan Perot and Emmanuelle Neumann and Jensen, {Anders A} and Lefebvre, {Sol{\`e}ne N} and Pierre-Jean Corringer and Jacques Neyton and Christophe Chipot and Francois Dehez and Guy Schoehn and Hugues Nury",

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doi = "10.1038/s41586-018-0672-3",

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T1 - Conformational transitions of the serotonin 5-HT3 receptor

AU - Polovinkin, Lucie

AU - Hassaine, Ghérici

AU - Perot, Jonathan

AU - Neumann, Emmanuelle

AU - Jensen, Anders A

AU - Lefebvre, Solène N

AU - Corringer, Pierre-Jean

AU - Neyton, Jacques

AU - Chipot, Christophe

AU - Dehez, Francois

AU - Schoehn, Guy

AU - Nury, Hugues

PY - 2018/11/8

Y1 - 2018/11/8

N2 - The serotonin 5-HT3 receptor is a pentameric ligand-gated ion channel (pLGIC). It belongs to a large family of receptors that function as allosteric signal transducers across the plasma membrane1,2; upon binding of neurotransmitter molecules to extracellular sites, the receptors undergo complex conformational transitions that result in transient opening of a pore permeable to ions. 5-HT3 receptors are therapeutic targets for emesis and nausea, irritable bowel syndrome and depression3. In spite of several reported pLGIC structures4-8, no clear unifying view has emerged on the conformational transitions involved in channel gating. Here we report four cryo-electron microscopy structures of the full-length mouse 5-HT3 receptor in complex with the anti-emetic drug tropisetron, with serotonin, and with serotonin and a positive allosteric modulator, at resolutions ranging from 3.2 Å to 4.5 Å. The tropisetron-bound structure resembles those obtained with an inhibitory nanobody5 or without ligand9. The other structures include an 'open' state and two ligand-bound states. We present computational insights into the dynamics of the structures, their pore hydration and free-energy profiles, and characterize movements at the gate level and cation accessibility in the pore. Together, these data deepen our understanding of the gating mechanism of pLGICs and capture ligand binding in unprecedented detail.

AB - The serotonin 5-HT3 receptor is a pentameric ligand-gated ion channel (pLGIC). It belongs to a large family of receptors that function as allosteric signal transducers across the plasma membrane1,2; upon binding of neurotransmitter molecules to extracellular sites, the receptors undergo complex conformational transitions that result in transient opening of a pore permeable to ions. 5-HT3 receptors are therapeutic targets for emesis and nausea, irritable bowel syndrome and depression3. In spite of several reported pLGIC structures4-8, no clear unifying view has emerged on the conformational transitions involved in channel gating. Here we report four cryo-electron microscopy structures of the full-length mouse 5-HT3 receptor in complex with the anti-emetic drug tropisetron, with serotonin, and with serotonin and a positive allosteric modulator, at resolutions ranging from 3.2 Å to 4.5 Å. The tropisetron-bound structure resembles those obtained with an inhibitory nanobody5 or without ligand9. The other structures include an 'open' state and two ligand-bound states. We present computational insights into the dynamics of the structures, their pore hydration and free-energy profiles, and characterize movements at the gate level and cation accessibility in the pore. Together, these data deepen our understanding of the gating mechanism of pLGICs and capture ligand binding in unprecedented detail.

U2 - 10.1038/s41586-018-0672-3

DO - 10.1038/s41586-018-0672-3

M3 - Journal article

C2 - 30401839

SN - 0028-0836

VL - 563

SP - 275

EP - 279

JO - Nature

JF - Nature

IS - 7730

ER -

Conformational transitions of the serotonin 5-HT3 receptor

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