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 β3 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.
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Acknowledgements
This work was supported by the Medical Research Counsil, the Biotechnology and Biological Sciences Research Council and the Wellcome Trust. We thank A. Hosie, P. Thomas and M. Wilkins for helpful comments and H. Da Silva for technical assistance.
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Miller, P., Topf, M. & Smart, T. Mapping a molecular link between allosteric inhibition and activation of the glycine receptor. Nat Struct Mol Biol 15, 1084–1093 (2008). https://doi.org/10.1038/nsmb.1492
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DOI: https://doi.org/10.1038/nsmb.1492