AustralieFrV1, Main, Exploration, bibRecord, 000345

String method solution of the gating pathways for a pentameric ligand-gated ion channel.

Identifieur interne : 000345 ( Main/Exploration ); précédent : 000344; suivant : 000346

String method solution of the gating pathways for a pentameric ligand-gated ion channel.

Auteurs : Bogdan Lev [Australie] ; Samuel Murail [France] ; Frédéric Poitevin [États-Unis] ; Brett A. Cromer [Australie] ; Marc Baaden [France] ; Marc Delarue [France] ; Toby W. Allen [Australie]

Source :

Proceedings of the National Academy of Sciences of the United States of America [ 1091-6490 ] ; 2017.

RBID : pubmed:28487483

Abstract

Pentameric ligand-gated ion channels control synaptic neurotransmission by converting chemical signals into electrical signals. Agonist binding leads to rapid signal transduction via an allosteric mechanism, where global protein conformational changes open a pore across the nerve cell membrane. We use all-atom molecular dynamics with a swarm-based string method to solve for the minimum free-energy gating pathways of the proton-activated bacterial GLIC channel. We describe stable wetted/open and dewetted/closed states, and uncover conformational changes in the agonist-binding extracellular domain, ion-conducting transmembrane domain, and gating interface that control communication between these domains. Transition analysis is used to compute free-energy surfaces that suggest allosteric pathways; stabilization with pH; and intermediates, including states that facilitate channel closing in the presence of an agonist. We describe a switching mechanism that senses proton binding by marked reorganization of subunit interface, altering the packing of β-sheets to induce changes that lead to asynchronous pore-lining M2 helix movements. These results provide molecular details of GLIC gating and insight into the allosteric mechanisms for the superfamily of pentameric ligand-gated channels.

DOI: 10.1073/pnas.1617567114
PubMed: 28487483

Affiliations:

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<front><div type="abstract" xml:lang="en">Pentameric ligand-gated ion channels control synaptic neurotransmission by converting chemical signals into electrical signals. Agonist binding leads to rapid signal transduction via an allosteric mechanism, where global protein conformational changes open a pore across the nerve cell membrane. We use all-atom molecular dynamics with a swarm-based string method to solve for the minimum free-energy gating pathways of the proton-activated bacterial GLIC channel. We describe stable wetted/open and dewetted/closed states, and uncover conformational changes in the agonist-binding extracellular domain, ion-conducting transmembrane domain, and gating interface that control communication between these domains. Transition analysis is used to compute free-energy surfaces that suggest allosteric pathways; stabilization with pH; and intermediates, including states that facilitate channel closing in the presence of an agonist. We describe a switching mechanism that senses proton binding by marked reorganization of subunit interface, altering the packing of β-sheets to induce changes that lead to asynchronous pore-lining M2 helix movements. These results provide molecular details of GLIC gating and insight into the allosteric mechanisms for the superfamily of pentameric ligand-gated channels.</div>
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String method solution of the gating pathways for a pentameric ligand-gated ion channel.

String method solution of the gating pathways for a pentameric ligand-gated ion channel.

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Abstract

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