Download MendeleyStructure of the pentameric ligand-gated ion channel ELIC cocrystallized with its competitive antagonist acetylcholine.
Pan, J., Chen, Q., Willenbring, D., Yoshida, K., Tillman, T., Kashlan, O.B., Cohen, A., Kong, X.P., Xu, Y., Tang, P.(2012) Nat Commun 3: 714-714
- PubMed: 22395605
- DOI: https://doi.org/10.1038/ncomms1703
- Primary Citation of Related Structures:
3RQU, 3RQW - PubMed 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.
Organizational Affiliation:
Department of Anesthesiology, 2057 Biomedical Science Tower 3, 3501 Fifth Avenue, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260, USA.
