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

Jianjun Pan, Qiang Chen, Dan Willenbring, Ken Yoshida, Tommy Tillman, Ossama B. Kashlan, Aina Cohen, Xiang-Peng Kong, Yan Xu and Pei Tang ()
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Jianjun Pan: 2057 Biomedical Science Tower 3, 3501 Fifth Avenue, University of Pittsburgh School of Medicine
Qiang Chen: 2057 Biomedical Science Tower 3, 3501 Fifth Avenue, University of Pittsburgh School of Medicine
Dan Willenbring: 2057 Biomedical Science Tower 3, 3501 Fifth Avenue, University of Pittsburgh School of Medicine
Ken Yoshida: 2057 Biomedical Science Tower 3, 3501 Fifth Avenue, University of Pittsburgh School of Medicine
Tommy Tillman: 2057 Biomedical Science Tower 3, 3501 Fifth Avenue, University of Pittsburgh School of Medicine
Ossama B. Kashlan: S931 Scaife, 3550 Terrace St, University of Pittsburgh School of Medicine
Aina Cohen: Stanford Synchrotron Radiation Lightsource
Xiang-Peng Kong: 550 First Avenue, MSB 329, New York University School of Medicine
Yan Xu: 2057 Biomedical Science Tower 3, 3501 Fifth Avenue, University of Pittsburgh School of Medicine
Pei Tang: 2057 Biomedical Science Tower 3, 3501 Fifth Avenue, University of Pittsburgh School of Medicine

Nature Communications, 2012, vol. 3, issue 1, 1-8

Abstract: Abstract 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.

Date: 2012
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DOI: 10.1038/ncomms1703

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