Structural Basis of Alcohol Inhibition of the Pentameric Ligand-Gated Ion Channel ELIC.

Autor: Chen Q; Department of Anesthesiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA., Wells MM; Department of Anesthesiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA; Department of Computational and System Biology, University of Pittsburgh, Pittsburgh, PA 15260, USA., Tillman TS; Department of Anesthesiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA., Kinde MN; Department of Anesthesiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA., Cohen A; Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, Menlo Park, CA 94025, USA., Xu Y; Department of Anesthesiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15260, USA; Department of Structural Biology, University of Pittsburgh, Pittsburgh, PA 15260, USA., Tang P; Department of Anesthesiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15260, USA; Department of Computational and System Biology, University of Pittsburgh, Pittsburgh, PA 15260, USA. Electronic address: ptang@pitt.edu.
Jazyk: angličtina
Zdroj: Structure (London, England : 1993) [Structure] 2017 Jan 03; Vol. 25 (1), pp. 180-187. Date of Electronic Publication: 2016 Dec 01.
DOI: 10.1016/j.str.2016.11.007
Abstrakt: The structural basis for alcohol modulation of neuronal pentameric ligand-gated ion channels (pLGICs) remains elusive. We determined an inhibitory mechanism of alcohol on the pLGIC Erwinia chrysanthemi (ELIC) through direct binding to the pore. X-ray structures of ELIC co-crystallized with 2-bromoethanol, in both the absence and presence of agonist, reveal 2-bromoethanol binding in the pore near T237(6') and the extracellular domain (ECD) of each subunit at three different locations. Binding to the ECD does not appear to contribute to the inhibitory action of 2-bromoethanol and ethanol as indicated by the same functional responses of wild-type ELIC and mutants. In contrast, the ELIC-α1β3GABA A R chimera, replacing the ELIC transmembrane domain (TMD) with the TMD of α1β3GABA A R, is potentiated by 2-bromoethanol and ethanol. The results suggest a dominant role of the TMD in modulating alcohol effects. The X-ray structures and functional measurements support a pore-blocking mechanism for inhibitory action of short-chain alcohols.
Competing Interests: The authors declare no conflicts of interest with the contents of this article.
(Copyright © 2016 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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