Structural basis of open channel block in a prokaryotic pentameric ligand-gated ion channel

Hilf, R.J.C.; Bertozzi, Carlo; Zimmermann, Iwan; Reiter, Alwin; Trauner, Dirk; Dutzler, Raimund

doi:10.1038/nsmb.1933

Cited by 91 publications

(109 citation statements)

References 39 publications

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“…Furthermore, it has been recently shown that lidocaine, and other quaternary ammonium compounds, also blocks prokaryotic pentameric ligand-gated channels (GLIC, protein from Gloeobacter violaceous), by its binding within the channel pore, causing a voltage-dependent blockade (Hilf et al, 2010), which is something similar to that we found for neuronal nAChRs from SCG neurons.…”

Section: Discussionsupporting

confidence: 74%

Lidocaine effects on acetylcholine-elicited currents from mouse superior cervical ganglion neurons

Alberola-Die

Reboreda

Lamas

et al. 2013

Neuroscience Research

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Section: Discussionsupporting

confidence: 74%

Lidocaine effects on acetylcholine-elicited currents from mouse superior cervical ganglion neurons

Alberola-Die

Reboreda

Lamas

et al. 2013

Neuroscience Research

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“…6C) (59,64), and at −2′ position for Zn 2+ and Cd 2+ (wheat sphere, Fig. 6C) (64). The −2′ pore site, which forms the ion selectivity filter, also overlaps with the picrotoxinin binding site in open GluCl (30).…”

Section: Discussionmentioning

confidence: 99%

“…6C) (64), at the 2′ position for Cs + (red sphere, Fig. 6C) (59,64), and at −2′ position for Zn 2+ and Cd 2+ (wheat sphere, Fig. 6C) (64).…”

Section: Discussionmentioning

confidence: 99%

“…Different pore blocker sites have been identified in open GLIC, including at the 13′ position for bromo-lidocaine (brown sphere, Fig. 6C) (64), at the 6′ position for tetraethylarsonium (light blue sphere, Fig. 6C) (64), at the 2′ position for Cs + (red sphere, Fig.…”

Section: Discussionmentioning

confidence: 99%

“…6C) (64), at the 6′ position for tetraethylarsonium (light blue sphere, Fig. 6C) (64), at the 2′ position for Cs + (red sphere, Fig. 6C) (59,64), and at −2′ position for Zn 2+ and Cd 2+ (wheat sphere, Fig.…”

Section: Discussionmentioning

confidence: 99%

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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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Foundations of Biomolecular Simulations: A Critical Introduction to Homology Modeling, Molecular Dynamics Simulations, and Free Energy Calculations of Membrane Proteins

Hénin

Baaden

Taly

2014

Membrane Proteins Production for Structural Analysis

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Structural basis of open channel block in a prokaryotic pentameric ligand-gated ion channel

Cited by 91 publications

References 39 publications

Lidocaine effects on acetylcholine-elicited currents from mouse superior cervical ganglion neurons

Lidocaine effects on acetylcholine-elicited currents from mouse superior cervical ganglion neurons

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

Foundations of Biomolecular Simulations: A Critical Introduction to Homology Modeling, Molecular Dynamics Simulations, and Free Energy Calculations of Membrane Proteins

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