Aricept Complexed with Acetylcholinesterase
From Proteopedia
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<applet load='1eve.pdb' size='500' frame='true' align='right' scene='Main_Page/E2020_in_ache_spinning/1' /> | <applet load='1eve.pdb' size='500' frame='true' align='right' scene='Main_Page/E2020_in_ache_spinning/1' /> | ||
==Results== | ==Results== | ||
| - | The X-ray structure of the E2020-''Tc''AChE complex shows that E2020 has a <scene name='1eve/E2020_close_up_with_84_279/ | + | The X-ray structure of the E2020-''Tc''AChE complex shows that E2020 has a <scene name='1eve/E2020_close_up_with_84_279/13'>unique orientation</scene> along the active-site gorge, extending from the anionic subsite (<scene name='1eve/E2020_close_up_with_84lbld/7'>W84</scene>) of the active site, at the bottom, to the peripheral anionic site (<scene name='1eve/E2020_close_up_with_84_279lbld/5'>near W279</scene>), 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 <scene name='1eve/E20_interactionshown/8'>indirectly via solvent molecules</scene>. |
==Conclusions== | ==Conclusions== | ||
Revision as of 07:44, 31 December 2009
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| 1eve, resolution 2.50Å () | |||||||||
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| Ligands: | , | ||||||||
| Activity: | Acetylcholinesterase, with EC number 3.1.1.7 | ||||||||
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| Resources: | FirstGlance, OCA, RCSB, PDBsum | ||||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||||
3D structure of anti-Alzheimer's drug, Aricept, complexed with acetylcholinesterase
(see also AChE bivalent inhibitors (Part II))
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.
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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 structure 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. 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
See 1eve (Chinese), 1eve (French), 1eve (Arabic), 1eve (Russian), 1eve (Spanish), & 1eve (Turkish).
Proteopedia Page Contributors and Editors (what is this?)
Eran Hodis, Joel L. Sussman, Jaime Prilusky, Alexander Berchansky, OCA, Michal Harel, David Canner, Wayne Decatur, Pham Ngoc Phuong, Angel Herraez, Lucie Kolarova
