Structural Basis for a Bimodal Allosteric Mechanism of General Anesthetic Modulation in Pentameric Ligand-Gated Ion Channels

• DOI: 10.1016/j.celrep.2018.03.108
• Publication Date: 2018-04-25T08:07:29Z
• Authors: Zaineb Fourati; Rebecca J. Howard; Stephanie A. Heusser; Haidai Hu; Reinis R. Ruza; Ludovic Sauguet; Erik Lindahl; Marc Delarue
• Keywords: General Anesthetics

Ion channel modulation by general anesthetics is a vital pharmacological process with implications for receptor biophysics and drug development. Functional studies have implicated conserved sites of both potentiation inhibition in pentameric ligand-gated ion channels, but detailed structural mechanism these bimodal effects lacking. The prokaryotic model protein GLIC recapitulates anesthetic human it accessible to structure determination apparent open closed states. Here, we report ten X-ray structures electrophysiological characterization variants the presence absence anesthetics, including surgical agent propofol. We show that can allosterically favor channels binding pore or via various subsites transmembrane domain. Our results support an integrated, multi-site allosteric modulation, they provide atomic details one most common anesthetics.