Structure Report for: 2ACE

This entry at resolution 2.5 A superseeds 1ACE

Title: Structure of acetylcholinesterase complexed with the nootropic alkaloid, (-)-huperzine A
Raves ML, Harel M, Pang YP, Silman I, Kozikowski AP, Sussman JL
Ref: Nat Struct Biol, 4:57, 1997 : PubMed
Abstract


ESTHER: Raves_1997_Nat.Struct.Biol_4_57
PubMedSearch: Raves 1997 Nat.Struct.Biol 4 57
PubMedID: 8989325
Gene_locus related to this paper: torca-ACHE

Abstract

(-)-Huperzine A (HupA) is found in an extract from a club moss that has been used for centuries in Chinese folk medicine. Its action has been attributed to its ability to strongly inhibit acetylcholinesterase (AChE). The crystal structure of the complex of AChE with optically pure HupA at 2.5 A resolution shows an unexpected orientation for the inhibitor with surprisingly few strong direct interactions with protein residues to explain its high affinity. This structure is compared to the native structure of AChE devoid of any inhibitor as determined to the same resolution. An analysis of the affinities of structural analogues of HupA, correlated with their interactions with the protein, shows the importance of individual hydrophobic interactions between HupA and aromatic residues in the active-site gorge of AChE.



        

Title: Atomic structure of acetylcholinesterase from Torpedo californica: a prototypic acetylcholine-binding protein
Sussman JL, Harel M, Frolow F, Oefner C, Goldman A, Toker L, Silman I
Ref: Science, 253:872, 1991 : PubMed
Abstract


ESTHER: Sussman_1991_Science_253_872
PubMedSearch: Sussman 1991 Science 253 872
PubMedID: 1678899
Gene_locus related to this paper: torca-ACHE

Abstract

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 alpha/beta protein that contains 537 amino acids. It consists of a 12-stranded mixed beta sheet surrounded by 14 alpha 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.