Structure and Function of ELIC Bound with the Antagonist Acetylcholine

Abstract

The bacterium Erwinia chrysanthemi ligand gated ion channel (ELIC) is a prototype for Cys-loop receptors, including nicotinic acetylcholine receptors (nAChRs). We co-crystallized ELIC with acetylcholine, an endogenous agonist of nAChRs, and solved the crystal structure to a resolution of 2.9 A. Acetylcholine binds to the orthosteric agonist site for Cys-loop receptors. Upon acetylcholine binding, loop C exhibits a substantial contraction with a profound reduction in flexibility. Conformational changes in nearby regions of the ligand-binding domain are also observed. However, no substantial reorganization in the pore region was identified except for subtle side chain reorientation of the pore constriction residue F247. Functional measurements on Xenopus oocytes expressing ELIC channels indicate that acetylcholine antagonizes the ELIC currents elicited by primary amines. Our high-resolution structure provides an atomic-level detailed picture of how ligand binding renders gating-related conformational changes in different domains of Cys-loop receptors. It also represents a valuable template for rational drug development. (Supported by NIH grants R01GM066358, R01GM056257, R37GM049202, and T32GM075770)