Article abstract
Nature Structural & Molecular Biology 15, 1084 - 1093 (2008)
Published online: 21 September 2008 | doi:10.1038/nsmb.1492
Mapping a molecular link between allosteric inhibition and activation of the glycine receptor
Paul S Miller1, Maya Topf2 & Trevor G Smart1
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 
3 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.
- Department of Pharmacology, University College London, Gower Street, London WC1E 6BT, UK.
- School of Crystallography, Birkbeck College, Malet Street, London WC1E 7HX, UK.
Correspondence to: Trevor G Smart1 e-mail: t.smart@ucl.ac.uk
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