Article thumbnail
Location of Repository

Mapping a molecular link between allosteric inhibition and activation of the glycine receptor

By P.S. Miller, Maya Topf and T.G. Smart

Abstract

Cys-loop ligand-gated ion channels mediate rapid neurotransmission throughout the central nervous system. They possess agonist recognition sites and allosteric sites where modulators regulate ion channel function. Using strychnine-sensitive glycine receptors, we identified a scaffold of hydrophobic residues enabling allosteric communication between glycine-agonist binding loops A and D, and the Zn2+-inhibition site. Mutating these hydrophobic residues disrupted Zn2+ inhibition, generating novel Zn2+-activated receptors and spontaneous channel activity. Homology modeling and electrophysiology revealed that these phenomena are caused by disruption to three residues on the '-' loop face of the Zn2+-inhibition site, and to D84 and D86, on a neighboring beta3 strand, forming a Zn2+-activation site. We provide a new view for the activation of a Cys-loop receptor where, following agonist binding, the hydrophobic core and interfacial loops reorganize in a concerted fashion to induce downstream gating

Topics: bcs
Publisher: Nature Publishing Group
Year: 2008
OAI identifier: oai:eprints.bbk.ac.uk.oai2:1143
Download PDF:
Sorry, we are unable to provide the full text but you may find it at the following location(s):
  • http://doi.org/10.1038/nsmb.14... (external link)
  • Suggested articles


    To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.