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Department of Biochemistry

Pentameric Ligand-Gated Ion Channels

The Pentameric Ligand-Gated Ion Channels (pLGICs) are members of a large protein family, which includes inontropic receptors for the neurotransmitters acetylcholine, serotonine, GABA and glycine10.

By studying close prokaryotic homologues, our work has provided the first structural insight into the family at high resolution. We have determined the structures of two homologues in different states by X-ray crystallography, the ligand-gated ion channel ELIC in a closed11 and the pH gated ion channel GLIC in an open state12. By using electrophysiology, we have identified the unknown ligands activating ELIC13, and we studied the mechanism of cation selectivity and inhibition by combining X-ray crystallography and electrophysiology14,15. Finally, we have investigated the mechanism of activation by studying the role of residues at the interface between the ligand-binding extracellular domain and the pore domain16. The research on this family was supported by grants of the NCCR Structural Biology and the Swiss National Science Foundation.

csm_Dutzler2018_fig3_a0518289e1

10    Hilf, R. J. & Dutzler, R. A prokaryotic perspective on pentameric ligand-gated ion channel structure. Curr. Opin. Struct. Biol. 19, 418-424 (2009).
11    Hilf, R. J. & Dutzler, R. X-ray structure of a prokaryotic pentameric ligand-gated ion channel. Nature 452, 375-379 (2008).
12    Hilf, R. J. & Dutzler, R. Structure of a potentially open state of a proton-activated pentameric ligand-gated ion channel. Nature 457, 115-118 (2009).
13    Zimmermann, I. & Dutzler, R. Ligand activation of the prokaryotic pentameric ligand-gated ion channel ELIC. PLoS Biol. 9, e1001101, doi:10.1371/journal.pbio.1001101 (2011).
14    Hilf, R. J. et al. Structural basis of open channel block in a prokaryotic pentameric ligand-gated ion channel. Nat. Struct. Mol. Biol. 17, 1330-1336 (2010).
15    Zimmermann, I., Marabelli, A., Bertozzi, C., Sivilotti, L. G. & Dutzler, R. Inhibition of the prokaryotic pentameric ligand-gated ion channel ELIC by divalent cations. PLoS Biol. 10, e1001429, doi:10.1371/journal.pbio.1001429 (2012).
16    Bertozzi, C., Zimmermann, I., Engeler, S., Hilf, R. J. & Dutzler, R. Signal Transduction at the Domain Interface of Prokaryotic Pentameric Ligand-Gated Ion Channels. PLoS Biol. 14, e1002393, doi:10.1371/journal.pbio.1002393 (2016).