X-ray structure of the mouse serotonin 5-HT3 receptor

Hassaı̈ne, Ghérici; Deluz, Cédric; Grasso, Luigino; Wyss, Romain; Tol, Menno B.; Hovius, Ruud; Graff, Alexandra; Stahlberg, Henning; Tanaka, Takashi; Desmyter, Aline; Moreau, Christophe; Li, Xiaodan; Poitevin, Frédéric; Vogel, Horst; Nury, Hugues

doi:10.1038/nature13552

Cited by 365 publications

(492 citation statements)

References 73 publications

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“…Interestingly, the above residues at the interface of the ECD and membrane have been shown to play significant role to the signal transduction that leads to the channel gating (10,50,51). However, the extend of the interacting network in the α2-Epi structure is smaller compared with homologous structures (15,21,22), probably signifying the intrinsic flexibility of the membrane-facing loops. …”

Section: Resultsmentioning

confidence: 84%

“…Following this need, structural studies of the nAChR have been the focus of numerous laboratories, leading to the achievement of many breakthroughs, such as the cryo-electron microscopy structure of the Torpedo nAChR (10) and the X-ray crystal structures of acetylcholine binding proteins (AChBPs; homologs of the ECD of nAChR) (11)(12)(13), mouse muscle-type α1 and human neuronal α9 nAChR ECDs (14,15), GLIC and ELIC (two prokaryotic homologs of pLGICs) (16,17), and two α7 nAChR ECD-AChBP chimeras (18,19). In addition, the structures of other members of the superfamily have recently become available, including that of an invertebrate anionic glutamate receptor (20), the human GABA A β3 (21), the mouse 5-HT 3 receptor (22), the human α3 glycine receptor (23), and the zebrafish α1 glycine receptor (24).…”

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confidence: 99%

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Crystal structure of a human neuronal nAChR extracellular domain in pentameric assembly: Ligand-bound α2 homopentamer

Kouvatsos

Giastas

Chroni-Tzartou

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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In this study we report the X-ray crystal structure of the extracellular domain (ECD) of the human neuronal α2 nicotinic acetylcholine receptor (nAChR) subunit in complex with the agonist epibatidine at 3.2 Å. Interestingly, α2 was crystallized as a pentamer, revealing the intersubunit interactions in a wild type neuronal nAChR ECD and the full ligand binding pocket conferred by two adjacent α subunits. The pentameric assembly presents the conserved structural scaffold observed in homologous proteins, as well as distinctive features, providing unique structural information of the binding site between principal and complementary faces. Structure-guided mutagenesis and electrophysiological data confirmed the presence of the α2(+)/α2(−) binding site on the heteromeric low sensitivity α2β2 nAChR and validated the functional importance of specific residues in α2 and β2 nAChR subunits. Given the pathological importance of the α2 nAChR subunit and the high sequence identity with α4 (78%) and other neuronal nAChR subunits, our findings offer valuable information for modeling several nAChRs and ultimately for structurebased design of subtype specific drugs against the nAChR associated diseases.cys-loop receptors | α2β2 nAChR | X-ray crystallography | ligand-gated ion channel

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Section: Resultsmentioning

confidence: 84%

mentioning

confidence: 99%

Crystal structure of a human neuronal nAChR extracellular domain in pentameric assembly: Ligand-bound α2 homopentamer

Kouvatsos

Giastas

Chroni-Tzartou

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…The number of clusters used for homomeric receptors was 124 (␣1 K24ЈA , 4 patches) and 69 (␣1 QϪ26ЈE/K24ЈA , 8 patches) and for heteromeric receptors was 114 (␣1␤ K24ЈA , 7 patches) and 76 (␣1 QϪ26ЈE -␤ K24ЈA , 9 patches). ***, p Ͻ 0.0001; **, p Ͻ 0.001; *, p Ͻ 0.01. eukaryotic (14,16,20,21) pLGICs. Given that these structures are static representations obtained under non-physiological conditions, it is vital to check them against functional data to ascertain if the crystal structures correspond to functionally relevant states.…”

Section: K24јamentioning

confidence: 99%

Correlating Structural and Energetic Changes in Glycine Receptor Activation

Scott

Lynch

Keramidas

2015

Journal of Biological Chemistry

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Background: Interactions between GlnϪ26Ј (in M1 domain), Arg 19Ј (in M2 domain), and Lys 24Ј (in M2-M3 linker) may reveal molecular mechanisms of glycine receptor activation. Results: ␣1QϪ26ЈE -containing receptors have longer active periods and lower conductances. Conclusion:The energy for activation is distributed broadly at the transduction zone. Significance: These energetic interactions are likely present in multiple pentameric ligand-gated ion channels.

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“…Our results demonstrate that the different allosteric binding sites present in Cys-loop receptors form an almost continuous path stretching from top to bottom of the receptor. (33). More recently, the cryo-EM structure of the α1 GlyR was determined in closed, open, and desensitized conformations (34).…”

mentioning

confidence: 99%

Allosteric binding site in a Cys-loop receptor ligand-binding domain unveiled in the crystal structure of ELIC in complex with chlorpromazine

Nys

Wijckmans

Farinha

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Pentameric ligand-gated ion channels or Cys-loop receptors are responsible for fast inhibitory or excitatory synaptic transmission. The antipsychotic compound chlorpromazine is a widely used tool to probe the ion channel pore of the nicotinic acetylcholine receptor, which is a prototypical Cys-loop receptor. In this study, we determine the molecular determinants of chlorpromazine binding in the Erwinia ligand-gated ion channel (ELIC). We report the X-ray crystal structures of ELIC in complex with chlorpromazine or its brominated derivative bromopromazine. Unexpectedly, we do not find a chlorpromazine molecule in the channel pore of ELIC, but behind the β8-β9 loop in the extracellular ligand-binding domain. The β8-β9 loop is localized downstream from the neurotransmitter binding site and plays an important role in coupling of ligand binding to channel opening. In combination with electrophysiological recordings from ELIC cysteine mutants and a thiol-reactive derivative of chlorpromazine, we demonstrate that chlorpromazine binding at the β8-β9 loop is responsible for receptor inhibition. We further use molecular-dynamics simulations to support the X-ray data and mutagenesis experiments. Together, these data unveil an allosteric binding site in the extracellular ligand-binding domain of ELIC. Our results extend on previous observations and further substantiate our understanding of a multisite model for allosteric modulation of Cys-loop receptors.ligand-gated ion channel | X-ray crystallography | allosteric modulation | Cys-loop receptor | nicotinic acetylcholine receptor C hlorpromazine (CPZ) (Fig. 1), a phenothiazine-derived antipsychotic drug, was introduced in psychiatry in the early 1950s, revolutionizing the treatment of psychotic disorders (1, 2). The main mechanism of action of CPZ consists in the blockage of dopamine receptors (2-4), but the numerous side effects associated with this drug indicate that it interacts with other physiologically relevant targets. CPZ was indeed shown to interfere with several voltage-and ligand-gated channels: it inhibits neuronal voltage-gated K + channels (5-7), BK Ca channels (8), and the human α 1E subunit-mediated Ca 2+ channels (9); CPZ was also shown to inhibit GABAergic currents (10, 11), specifically through GABA A receptors (GABA A Rs) (12), and to inhibit serotonin type-3 receptors (5-HT 3 Rs) (13, 14) and nicotinic acetylcholine receptors (nAChRs) (15, 16), members of the Cys-loop receptor family.The Cys-loop receptor family is composed of membranespanning ligand-gated ion channels that are responsible for fast excitatory or inhibitory synaptic neurotransmission. They are composed of five identical or nonidentical subunits, each of them comprising an N-terminal extracellular domain, which contains the neurotransmitter binding site, four transmembrane helices, that when assembled allow ions to pass through the membrane, and an intracellular domain, responsible for channel conductance, receptor modulation, and trafficking (17, 18). Initial structural insight into the ...

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X-ray structure of the mouse serotonin 5-HT3 receptor

Cited by 365 publications

References 73 publications

Crystal structure of a human neuronal nAChR extracellular domain in pentameric assembly: Ligand-bound α2 homopentamer

Crystal structure of a human neuronal nAChR extracellular domain in pentameric assembly: Ligand-bound α2 homopentamer

Correlating Structural and Energetic Changes in Glycine Receptor Activation

Allosteric binding site in a Cys-loop receptor ligand-binding domain unveiled in the crystal structure of ELIC in complex with chlorpromazine

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