Un-gating and allosteric modulation of a pentameric ligand-gated ion channel captured by molecular dynamics

Martin, Nicolas Éric; Malik, Siddharth; Calimet, Nicolas; Changeux, Jean‐Pierre; Cecchini, Marco

doi:10.1371/journal.pcbi.1005784

Cited by 34 publications

(58 citation statements)

References 51 publications

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“…Interestingly, this annotation supports the conclusion that pore constriction or the gate is located differently in resting versus desensitized channels, which is consistent with recent mutagenesis and kinetic experiments (Gielen et al, 2015). Also, it suggests that pore closing by desensitization versus channel deactivation or ungating (Martin et al, 2017) would involve the polar reorientation of the pore-lining helices M2 in opposite directions, i.e., an inward untilting to straighten for deactivation, and further tilting in the outward direction for desensitization.…”

Section: Conclusion On the Wide-open And The Semi-open Structures Ofsupporting

confidence: 88%

An Ion-Permeable State of the Glycine Receptor Captured by Molecular Dynamics

2018

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Glycine receptors (GlyR) mediate fast inhibitory neurotransmission by switching between discrete states in response to ligand-binding events. Recent high-resolution structures from cryoelectron microscopy (cryo-EM) and X-ray crystallography have provided atomistic models for the open and closed states. Notably, the cryo-EM structure in complex with glycine illuminated a previously unreported wide-open state, whose physiological significance is debated. Here, we present the structure of an ion-conducting state of GlyR α1 captured by molecular dynamics and validate its physiological relevance with computational electrophysiology and polyatomic anion permeation simulations. Our analysis suggests that none of the experimental structures is a true representation of the physiologically active state, although previously characterized open channels in GLIC at pH 4, or GluCl/GlyR with ivermectin bound, provide reasonable models. These results open the door to an original functional annotation and support the conclusion that pore closing by desensitization versus deactivation involves the reorientation of the pore-lining helices in opposite directions.

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Section: Conclusion On the Wide-open And The Semi-open Structures Ofsupporting

confidence: 88%

An Ion-Permeable State of the Glycine Receptor Captured by Molecular Dynamics

2018

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“…As a cautionary note, the interpretation of MD trajectories relies on the assignment of functional states to the structures used as starting points for the simulations, and it has been proposed that the initial GLIC and GluCl structures might represent desensitized states (Akabas, 2013). Still, recent molecular dynamics suggests that the main quaternary event concomitant with channel opening lies in the twisting (Martin et al 2017). This quaternary motion is coupled to a tilt of the M2 pore-lining helices, yielding a widening of the upper part of the channel that carries the activation gate.…”

Section: Gating Mechanism and Permeation Determinants Of Plgicsmentioning

confidence: 99%

“…Still, recent molecular dynamics suggests that the main quaternary event concomitant with channel opening lies in the twisting (Martin et al . ). This quaternary motion is coupled to a tilt of the M2 pore‐lining helices, yielding a widening of the upper part of the channel that carries the activation gate.…”

Section: Introductionmentioning

confidence: 97%

The dual‐gate model for pentameric ligand‐gated ion channels activation and desensitization

Gielen

Corringer

2018

The Journal of Physiology

102

122

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Pentameric ligand-gated ion channels (pLGICs) mediate fast neurotransmission in the nervous system. Their dysfunction is associated with psychiatric, neurological and neurodegenerative disorders such as schizophrenia, epilepsy and Alzheimer's disease. Understanding their biophysical and pharmacological properties, at both the functional and the structural level, thus holds many therapeutic promises. In addition to their agonist-elicited activation, most pLGICs display another key allosteric property, namely desensitization, in which they enter a shut state refractory to activation upon sustained agonist binding. While the activation mechanisms of several pLGICs have been revealed at near-atomic resolution, the structural foundation of desensitization has long remained elusive. Recent structural and functional data now suggest that the activation and desensitization gates are distinct, and are located at both sides of the ion channel. Such a 'dual gate mechanism' accounts for the marked allosteric effects of channel blockers, a feature illustrated herein by theoretical kinetics simulations. Comparison with other classes of ligand- and voltage-gated ion channels shows that this dual gate mechanism emerges as a common theme for the desensitization and inactivation properties of structurally unrelated ion channels.

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“…18 In that study, we used the open GluCl structure 31 as template, removing the positive allosteric modulator ivermectin present in the original structure. To avoid the pore collapse after ivermectin deletion, observed also by other authors, 32,58,81 we employed an initial restraint on the hydrophobic rings to pull apart the hydrophobic sidechains, thus creating a water-accessible volume in the pore.…”

Section: The Apo Conformationsmentioning

confidence: 99%

Closed-Locked and Apo-Resting State Structures of the Human α7 Nicotinic Receptor: A Computational Study

Chiodo

Malliavin

Giuffrida

et al. 2018

J. Chem. Inf. Model.

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Journal of Chemical Information and Modeling gated ion channels (LGICs), are membrane proteins present in neurons and at neuromuscular junctions. They are responsible for signal transmission, and their function is regulated by neurotransmitters, agonists and antagonists drugs. A detailed knowledge of their conformational transition in response to ligand binding is critical to understand the basis of ligand-receptor interaction, in view of new pharmacological approaches to control receptor activity. However, the scarcity of experimentally derived structures of human channels makes this perspective extremely challenging. To contribute overcoming this issue, we have recently reported structural models for the open and the desensitized states of the human α7 nicotinic receptor. Here, we provide all-atom structural models of the same receptor in two different non-conductive states. The first structure, built via homology modeling and relaxed with extensive Molecular Dynamics simulations, represents the receptor bound to the natural antagonist α-conotoxin ImI. After comparison with available experimental data and computational models of other eukaryotic LGICs, we deem it consistent with the "closed-locked" state. The second model, obtained with simulations from the spontaneous relaxation of the open, agonist-bound α7 structure after ligand removal, recapitulates the characteristics of the apo-resting state of the receptor. These results add to our previous work on the active and desensitized state conformations, contributing to the structural characterization of the conformational landscape of the human α7 receptor, and suggesting benchmarks to discriminate among conformations found in experiments or in simulations of LGICs. In particular key interactions at the interface between the extracellular domain and the transmembrane domain are identified, that could be critical to the α7 receptor function.

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Un-gating and allosteric modulation of a pentameric ligand-gated ion channel captured by molecular dynamics

Cited by 34 publications

References 51 publications

An Ion-Permeable State of the Glycine Receptor Captured by Molecular Dynamics

An Ion-Permeable State of the Glycine Receptor Captured by Molecular Dynamics

The dual‐gate model for pentameric ligand‐gated ion channels activation and desensitization

Closed-Locked and Apo-Resting State Structures of the Human α7 Nicotinic Receptor: A Computational Study

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