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Title: Structure of the pentameric ligand-gated ion channel ELIC cocrystallized with its competitive antagonist acetylcholine

Journal Article · · Nature Communications
DOI:https://doi.org/10.1038/ncomms1703· OSTI ID:1623898
 [1];  [1];  [1];  [1];  [1];  [2];  [3];  [4];  [5];  [6]
  1. Univ. of Pittsburgh, PA (United States). School of Medicine, Dept. of Anesthesiology
  2. Univ. of Pittsburgh, PA (United States). School of Medicine, Dept. of Medicine
  3. SLAC National Accelerator Lab., Menlo Park, CA (United States). Stanford Synchrotron Radiation Lightsource (SSRL)
  4. New York Univ. (NYU), NY (United States). School of Medicine, Dept. of Biochemistry
  5. Univ. of Pittsburgh, PA (United States). School of Medicine, Dept. of Anesthesiology; Univ. of Pittsburgh, PA (United States). School of Medicine, Dept. of Structural Biology; Univ. of Pittsburgh, PA (United States). School of Medicine, Dept. of Pharmacology and Chemical Biology
  6. Univ. of Pittsburgh, PA (United States). School of Medicine, Dept. of Anesthesiology; Univ. of Pittsburgh, PA (United States). School of Medicine, Dept. of Computational Biology; Univ. of Pittsburgh, PA (United States). School of Medicine, Dept. of Pharmacology and Chemical Biology
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ELIC, the pentameric ligand-gated ion channel from Erwinia chrysanthemi, is a prototype for Cys-loop receptors. Here we show that acetylcholine is a competitive antagonist for ELIC. We determine the acetylcholine–ELIC cocrystal structure to a 2.9-Å resolution and find that acetylcholine binding to an aromatic cage at the subunit interface induces a significant contraction of loop C and other structural rearrangements in the extracellular domain. The side chain of the pore-lining residue F247 reorients and the pore size consequently enlarges, but the channel remains closed. We attribute the inability of acetylcholine to activate ELIC primarily to weak cation-π and electrostatic interactions in the pocket, because an acetylcholine derivative with a simple quaternary-to-tertiary ammonium substitution activates the channel. This study presents a compelling case for understanding the structural underpinning of the functional relationship between agonism and competitive antagonism in the Cys-loop receptors, providing a new framework for developing novel therapeutic drugs.

Research Organization:
SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States). Stanford Synchrotron Radiation Lightsource (SSRL)
Sponsoring Organization:
USDOE Office of Science (SC), Biological and Environmental Research (BER)
Grant/Contract Number:
AC02-76SF00515
OSTI ID:
1623898
Journal Information:
Nature Communications, Vol. 3, Issue 1; ISSN 2041-1723
Publisher:
Nature Publishing GroupCopyright Statement
Country of Publication:
United States
Language:
English

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Inhibition of the Prokaryotic Pentameric Ligand-Gated Ion Channel ELIC by Divalent Cations text January 2012
Common Internal Allosteric Network Links Anesthetic Binding Sites in a Pentameric Ligand-Gated Ion Channel journal July 2016
The Nicotinic Acetylcholine Receptor: The Founding Father of the Pentameric Ligand-gated Ion Channel Superfamily journal November 2012
Inhibition of the Prokaryotic Pentameric Ligand-Gated Ion Channel ELIC by Divalent Cations journal November 2012
Pentameric ligand-gated ion channel ELIC is activated by GABA and modulated by benzodiazepines journal October 2012
Allosteric binding site in a Cys-loop receptor ligand-binding domain unveiled in the crystal structure of ELIC in complex with chlorpromazine journal October 2016
Mutagenesis computer experiments in pentameric ligand-gated ion channels: the role of simulation tools with different resolution journal April 2019
An outline of desensitization in pentameric ligand-gated ion channel receptors journal August 2012
Structural basis of neurosteroid anesthetic action on GABAA receptors journal September 2018
Structural Studies of GABAA Receptor Binding Sites: Which Experimental Structure Tells us What? journal June 2016
Direct interaction of the resistance to inhibitors of cholinesterase type 3 protein with the serotonin receptor type 3A intracellular domain journal March 2016
Direct Pore Binding as a Mechanism for Isoflurane Inhibition of the Pentameric Ligand-gated Ion Channel ELIC journal September 2015
A chimeric prokaryotic pentameric ligand–gated channel reveals distinct pathways of activation journal September 2015
Conformational Changes in Acetylcholine Binding Protein Investigated by Temperature Accelerated Molecular Dynamics journal February 2014
Molecular Recognition of the Neurotransmitter Acetylcholine by an Acetylcholine Binding Protein Reveals Determinants of Binding to Nicotinic Acetylcholine Receptors journal March 2014
A Structural Model of the Human α7 Nicotinic Receptor in an Open Conformation journal July 2015

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