ArticleProceedings of the National Academy of Sciences of the United States of America2016
Allosteric binding site in a Cys-loop receptor ligand-binding domain unveiled in the crystal structure of ELIC in complex with chlorpromazine.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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15 citing papers in PubMed, 32 citations in OpenAlex.
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- Mutagenesis computer experiments in pentameric ligand-gated ion channels: the role of simulation tools with different resolution.Interface focus · 2019Review
- Electrostatics, proton sensor, and networks governing the gating transition in GLIC, a proton-gated pentameric ion channel.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- Nicotinic acetylcholine receptors at the single-channel level.British journal of pharmacology · 2018Review
- Crystal structures of a pentameric ion channel gated by alkaline pH show a widely open pore and identify a cavity for modulation.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- An allosteric binding site of the α7 nicotinic acetylcholine receptor revealed in a humanized acetylcholine-binding protein.The Journal of biological chemistry · 2018Article
- Disruption of a Structurally Important Extracellular Element in the Glycine Receptor Leads to Decreased Synaptic Integration and Signaling Resulting in Severe Startle Disease.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2017Article
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Authors and funding
11 authors at 3 institutions in 2 countries.
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No grant is acknowledged in the PubMed record.
Abstract
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.
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