Structure of the pentameric ligand-gated ion channel ELIC cocrystallized with its competitive antagonist acetylcholine
- Univ. of Pittsburgh, PA (United States). School of Medicine, Dept. of Anesthesiology
- Univ. of Pittsburgh, PA (United States). School of Medicine, Dept. of Medicine
- SLAC National Accelerator Lab., Menlo Park, CA (United States). Stanford Synchrotron Radiation Lightsource (SSRL)
- New York Univ. (NYU), NY (United States). School of Medicine, Dept. of Biochemistry
- 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
- 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
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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