Crystal structure of mouse acetylcholinesterase - A peripheral site-occluding loop in a tetrameric assembly

The crystal structure of mouse acetylcholinesterase at 2.9-? resolution rev eals a tetrameric assembly of subunits with an antiparallel alignment of tw o canonical homodimers assembled through four-helix bundles. In the tetrame r, a short Omega loop, composed of a cluster of hydrophobic residues conser ved in mammalian acetylcholinesterases along with flanking alpha-helices, a ssociates with the peripheral anionic site of the facing subunit and steric ally occludes the entrance of the gorge leading to the active center. The i nverse loop-peripheral site interaction occurs within the second pair of su bunits, but the peripheral sites on the two loop-donor subunits remain free ly accessible to the solvent. The position and complementarity of the perip heral site-occluding loop mimic the characteristics of the central loop of the peptidic inhibitor fasciculin bound to mouse acetylcholinesterase, Tetr americ forms of cholinesterases are widely distributed in nature and predom inate in mammalian brain. This structure reveals a likely mode of subunit a rrangement and suggests that the peripheral site, located near the rim of t he gorge, is a site for association of neighboring subunits or heterologous proteins with interactive surface loops.