Unknown

Dataset Information

0

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


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 ?-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.

SUBMITTER: Lev B 

PROVIDER: S-EPMC5448215 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

altmetric image

Publications

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

Lev Bogdan B   Murail Samuel S   Poitevin Frédéric F   Cromer Brett A BA   Baaden Marc M   Delarue Marc M   Allen Toby W TW  

Proceedings of the National Academy of Sciences of the United States of America 20170509 21


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  ...[more]

Similar Datasets

| S-EPMC3833874 | biostudies-literature
| S-EPMC2770624 | biostudies-literature
| S-EPMC3801054 | biostudies-literature
| S-EPMC5673239 | biostudies-literature
| S-EPMC3021669 | biostudies-literature
| S-EPMC3119659 | biostudies-literature
| S-EPMC1312410 | biostudies-literature
| S-EPMC5550297 | biostudies-literature
| S-EPMC2941008 | biostudies-literature
| S-EPMC8449418 | biostudies-literature