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1eve
From Proteopedia
| , resolution 2.5Å | |
|---|---|
| Ligands: | |
| Activity: | Acetylcholinesterase, with EC number 3.1.1.7 |
| Resources: | FirstGlance, OCA, PDBsum, RCSB |
| Coordinates: | save as pdb, mmCIF, xml |
3D structure of anti-Alzheimer's drug, Aricept, complexed with acetylcholinesterase
Contents |
Background
Several cholinesterase inhibitors are either being utilized for symptomatic treatment of Alzheimer's disease or are in advanced clinical trials. E2020, marketed as Aricept, is a member of a large family of N-benzylpiperidine-based acetylcholinesterase (AChE) inhibitors, developed, synthesized and evaluated by the Eisai Company in Japan. These inhibitors were designed on the basis of QSAR studies prior to elucidation of the 3D structure of Torpedo californica AChE (TcAChE) (1ea5). It significantly enhances performance in animal models of cholinergic hypofunction and has a high affinity for AChE, binding to both electric eel and mouse AChE in the nanomolar range.
Results
The X-ray structure of the E2020-TcAChE complex shows that E2020 has a along the active-site gorge, extending from the anionic subsite () of the active site, at the bottom, to the peripheral anionic site (), at the top, via aromatic stacking interactions with conserved aromatic acid residues. E2020 does not, however, interact directly with either the catalytic triad or the 'oxyanion hole' but only .
Conclusions
The X-ray struture shows, a posteriori, that the design of E2020 took advantage of several important features of the active-site gorge of AChE, to produce a drug with both high affinity for AChE and a high degree of selectivity for AChE versus butyrylcholinesterase (BChE). It also delineates voids within the gorge that are not occupied by E2020 and could provide sites for potential modification of E2020 to produce drugs with improved pharmacological profiles.
About this Structure
1EVE is a Single protein structure of sequence from Torpedo californica with NAG and E20 as ligands. Active as Acetylcholinesterase, with EC number 3.1.1.7 Known active sites: CAT and IHB. Full crystallographic information is available from OCA.
Reference
Structure of acetylcholinesterase complexed with E2020 (Aricept): implications for the design of new anti-Alzheimer drugs., Kryger G, Silman I, Sussman JL, Structure. 1999 Mar 15;7(3):297-307. PMID:10368299
Page seeded by OCA on Thu Nov 8 12:39:55 2007
