Structure of the pentameric ligand-gated ion channel ELIC cocrystallized with its competitive antagonist acetylcholine

Pan, Jianjun; Chen, Qiang; Willenbring, Dan; Yoshida, Ken; Tillman, Tommy S.; Kashlan, Ossama B.; Cohen, Aina E.; Kong, Xiang‐Peng; Xu, Yan; Tang, Pei

doi:10.1038/ncomms1703

Cited by 95 publications

(146 citation statements)

References 45 publications

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“…Although this is perhaps not surprising given that the M4 C terminus in ELIC has primarily aliphatic residues, with Gly and Ile facing the M1/M3 interface, even deletion of the charged Arg-317 had no detrimental effect. As noted, the final 5 residues in the C-terminal half of M4 ␣-helix are not resolved in the ELIC crystal structure (34,35). The crystal structure suggests weak interactions between the M4 C terminus and either M1/M3 or the ␤6-␤7 loop.…”

Section: Error Bars Represent Sd (Glic) and Log Sd (Elic)mentioning

confidence: 86%

The M4 Transmembrane α-Helix Contributes Differently to Both the Maturation and Function of Two Prokaryotic Pentameric Ligand-gated Ion Channels

Hénault

Juranka

Baenziger

2015

Journal of Biological Chemistry

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Background:The role of the outermost M4 transmembrane ␣-helix in prokaryotic pentameric ligand-gated ion channel (pLGIC) function is unknown. Results: Interactions between the M4 C terminus and both the adjacent M3 ␣-helix and the ␤6-␤7 loop are essential in one, but not another prokaryotic pLGIC. Conclusion: M4 contributes differently to maturation/function. Significance: Variations in M4 may contribute to subunit-specific functional differences.

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Section: Error Bars Represent Sd (Glic) and Log Sd (Elic)mentioning

confidence: 86%

The M4 Transmembrane α-Helix Contributes Differently to Both the Maturation and Function of Two Prokaryotic Pentameric Ligand-gated Ion Channels

Hénault

Juranka

Baenziger

2015

Journal of Biological Chemistry

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“…However, the nAChR model from cryoelectron micrographs hugely benefits from the fact that these channels are in their native Torpedo membranes in contrast to the crystal structures of ELIC, GLIC, and GluCL, which are in a detergent-solubilized environment. There is also growing evidence that crystallization conditions may bias structures toward specific conformations (6,11,63). Gating in these channels is intrinsically modulated by membrane lipids (22,64,65), likely by an allosteric mechanism that alters the relay of communication through the interface between the ECD and the TMD.…”

Section: Discussionmentioning

confidence: 99%

Structural Basis for Allosteric Coupling at the Membrane-Protein Interface in Gloeobacter violaceus Ligand-gated Ion Channel (GLIC)

Velisetty

Chalamalasetti

Chakrapani

2014

Journal of Biological Chemistry

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Background: Allosteric mechanisms in ligand-gated ion-channels (pLGIC) that couple neurotransmitter binding to channel opening are poorly understood. GLIC is an important prokaryotic surrogate. Results: EPR studies at the junctional interface of GLIC reveal structural changes during desensitization. Conclusion:The closed conformation is characterized by extensive intrasubunit interactions at the junctional interface that weaken during desensitization. Significance: These studies elucidate the role of structural dynamics in pLGIC function.

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“…The availability of several relatively high-resolution X-ray cocrystal structures of ELIC in complex with known ligands renders this channel a relevant model for the study of Cys-loop receptor modulation (36,(38)(39)(40)(41)(42).…”

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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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Structure of the pentameric ligand-gated ion channel ELIC cocrystallized with its competitive antagonist acetylcholine

Cited by 95 publications

References 45 publications

The M4 Transmembrane α-Helix Contributes Differently to Both the Maturation and Function of Two Prokaryotic Pentameric Ligand-gated Ion Channels

The M4 Transmembrane α-Helix Contributes Differently to Both the Maturation and Function of Two Prokaryotic Pentameric Ligand-gated Ion Channels

Structural Basis for Allosteric Coupling at the Membrane-Protein Interface in Gloeobacter violaceus Ligand-gated Ion Channel (GLIC)

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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