Atomic Structure of Acetylcholinesterase from Torpedo californica : A Prototypic Acetylcholine-Binding Protein

• DOI: 10.1126/science.1678899
• Publication Date: 2006-10-05T22:10:16Z
• Authors: Joel L. Sussman; Michal Harel; Felix Frolow; Christian Oefner; Adrian Goldman; Lilly Toker; Israel Silman
• Keywords: Electric Organ; Binding Sites; Chemical Phenomena; Molecular Structure; Chemistry, Physical; Macromolecular Substances; Protein Conformation; Cell Membrane; Molecular Sequence Data; Glutamic Acid; Phosphatidylinositols; Torpedo; Acetylcholine; Glutamates; X-Ray Diffraction; Sequence Homology, Nucleic Acid; Acetylcholinesterase; Animals; Amino Acid Sequence; Crystallization

The three-dimensional structure of acetylcholinesterase from Torpedo californica electric organ has been determined by x-ray analysis to 2.8 angstrom resolution. The form crystallized is the glycolipid-anchored homodimer that was purified subsequent to solubilization with a bacterial phosphatidylinositol-specific phospholipase C. The enzyme monomer is an α/β protein that contains 537 amino acids. It consists of a 12-stranded mixed β sheet surrounded by 14 α helices and bears a striking resemblance to several hydrolase structures including dienelactone hydrolase, serine carboxypeptidase-II, three neutral lipases, and haloalkane dehalogenase. The active site is unusual because it contains Glu, not Asp, in the Ser-His-acid catalytic triad and because the relation of the triad to the rest of the protein approximates a mirror image of that seen in the serine proteases. Furthermore, the active site lies near the bottom of a deep and narrow gorge that reaches halfway into the protein. Modeling of acetylcholine binding to the enzyme suggests that the quaternary ammonium ion is bound not to a negatively charged "anionic" site, but rather to some of the 14 aromatic residues that line the gorge.