PDBsum entry 2w6c

Hydrolase

PDB id: 2w6c

Contents

Protein chain

528 a.a. *

Ligands

NAG-NAG

BM4

NAG ×2

Waters ×115

* Residue conservation analysis

PDB id:

2w6c

Name:

Hydrolase

Title:

Ache in complex with a bis-(-)-nor-meptazinol derivative

Structure:

Acetylcholinesterase. Chain: x. Synonym: ache. Ec: 3.1.1.7

Source:

Torpedo californica. Pacific electric ray. Organism_taxid: 7787. Organ: electric organ

Resolution:

2.69Å R-factor: 0.188 R-free: 0.235

Authors:

A.Paz,Q.Xie,H.M.Greenblatt,W.Fu,Y.Tang,I.Silman,Z.Qiu,J.L.Sussman

Key ref:

A.Paz et al. (2009). The crystal structure of a complex of acetylcholinesterase with a bis-(-)-nor-meptazinol derivative reveals disruption of the catalytic triad. J Med Chem, 52, 2543-2549. PubMed id: 19326912

Date:

18-Dec-08 Release date: 07-Apr-09

Protein chain

P04058  (ACES_TETCF) -  Acetylcholinesterase from Tetronarce californica

Seq: 586 a.a.

Struc: 528 a.a.

Enzyme reactions

• Enzyme class: E.C.3.1.1.7 - acetylcholinesterase.
• Reaction: acetylcholine + H2O = choline + acetate + H⁺

acetylcholine (Bound ligand (Het Group name = NAG) matches with 41.18% similarity) + H2O = choline + acetate + H(+)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

J Med Chem 52:2543-2549 (2009)

PubMed id: 19326912

The crystal structure of a complex of acetylcholinesterase with a bis-(-)-nor-meptazinol derivative reveals disruption of the catalytic triad.

A.Paz, Q.Xie, H.M.Greenblatt, W.Fu, Y.Tang, I.Silman, Z.Qiu, J.L.Sussman.

ABSTRACT

A bis-(-)-nor-meptazinol derivative in which the two meptazinol rings are linked by a nonamethylene spacer is a novel acetylcholinesterase inhibitor that inhibits both catalytic activity and Abeta peptide aggregation. The crystal structure of its complex with Torpedo californica acetylcholinesterase was determined to 2.7 A resolution. The ligand spans the active-site gorge, with one nor-meptazinol moiety bound at the "anionic" subsite of the active site, disrupting the catalytic triad by forming a hydrogen bond with His440N(epsilon2), which is hydrogen-bonded to Ser200O(gamma) in the native enzyme. The second nor-meptazinol binds at the peripheral "anionic" site at the gorge entrance. A number of GOLD models of the complex, using both native TcAChE and the protein template from the crystal structure of the bis-(-)-nor-meptazinol/TcAChE complex, bear higher similarity to the X-ray structure than a previous model obtained using the mouse enzyme structure. These findings may facilitate rational design of new meptazinol-based acetylcholinesterase inhibitors.