Format

Send to

Choose Destination
Structure. 2016 Apr 5;24(4):595-605. doi: 10.1016/j.str.2016.02.014. Epub 2016 Mar 24.

Sites of Anesthetic Inhibitory Action on a Cationic Ligand-Gated Ion Channel.

Author information

1
Laboratoire de Biochimie Théorique, CNRS, UPR9080, University Paris Diderot, Sorbonne Paris Cité, 13 rue Pierre et Marie Curie, 75005 Paris, France.
2
Unité de Dynamique Structurale des Macromolécules, Institut Pasteur, 75015 Paris, France.
3
Unité de Dynamique Structurale des Macromolécules, Institut Pasteur, 75015 Paris, France; UMR 3258, Centre National de la Recherche Scientifique, 75015 Paris, France.
4
Unité de Dynamique Structurale des Macromolécules, Institut Pasteur, 75015 Paris, France; UMR 3258, Centre National de la Recherche Scientifique, 75015 Paris, France. Electronic address: marc.delarue@pasteur.fr.
5
Laboratoire de Biochimie Théorique, CNRS, UPR9080, University Paris Diderot, Sorbonne Paris Cité, 13 rue Pierre et Marie Curie, 75005 Paris, France. Electronic address: baaden@smplinux.de.

Abstract

Pentameric ligand-gated ion channels have been identified as the principal target of general anesthetics (GA), whose molecular mechanism of action remains poorly understood. Bacterial homologs, such as the Gloeobacter violaceus receptor (GLIC), have been shown to be valid functional models of GA action. The GA bromoform inhibits GLIC at submillimolar concentration. We characterize bromoform binding by crystallography and molecular dynamics (MD) simulations. GLIC's open form structure identified three intra-subunit binding sites. We crystallized the locally closed form with an additional bromoform molecule in the channel pore. We systematically compare binding with the multiple potential sites of allosteric channel regulation in the open, locally closed, and resting forms. MD simulations reveal differential exchange pathways between sites from one form to the other. GAs predominantly access the receptor from the lipid bilayer in all cases. Differential binding affinity among the channel forms is observed; the pore site markedly stabilizes the inactive versus active state.

PMID:
27021161
DOI:
10.1016/j.str.2016.02.014
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center