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Publication Abstract from PubMed

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-A 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-pi 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.

Structure 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 OB, Cohen A, Kong XP, Xu Y, Tang P Nat Commun. 2012 Mar 6;3:714. doi: 10.1038/ncomms1703. PMID:22395605^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.