Sandbox uc 17
From Proteopedia
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| - | + | [[Image:E2020_interactins_in_AChE_gorge.jpg|left|250px]]<br /> | |
| + | {{STRUCTURE_1eve| PDB=1eve | SCENE=Main_Page/E2020_in_ache_spinning/1 }} | ||
| - | + | '''3D structure of anti-Alzheimer's drug, Aricept, complexed with acetylcholinesterase''' | |
| - | + | (see also [[AChE bivalent inhibitors (Part II)]]) | |
| + | ==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 (''Tc''AChE) ([[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. | ||
| - | < | + | {{Clear}} |
| + | <applet load='1eve.pdb' size='500' frame='true' align='right' scene='Main_Page/E2020_in_ache_spinning/1' /> | ||
| + | ==Results== | ||
| + | The X-ray structure of the E2020-''Tc''AChE complex shows that E2020 has a <scene name='1eve/E2020_close_up_with_84_279/13'>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== | ||
| + | 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 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Torpedo_californica Torpedo californica]. The June 2004 RCSB PDB [http://pdb.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/index.html Molecule of the Month] feature on ''Acetylcholinesterase'' by David S. Goodsell is [http://dx.doi.org/10.2210/rcsb_pdb/mom_2004_6 10.2210/rcsb_pdb/mom_2004_6]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1EVE OCA]. | ||
==Additional Resources== | ==Additional Resources== | ||
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==Reference== | ==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:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=10368299 10368299] | |
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| + | See [[1eve (Chinese)]], [[1eve (French)]], [[1eve (Arabic)]], [[1eve (Russian)]], [[1eve (Spanish)]], & [[1eve (Turkish)]]. | ||
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| + | [[ar:1eve (Arabic)]] | ||
| + | [[zh:1eve (Chinese)]] | ||
| + | [[fr:1eve (French)]] | ||
| + | [[de:1eve (German)]] | ||
| + | [[ru:1eve (Russian)]] | ||
| + | [[es:1eve (Spanish)]] | ||
| + | [[tr:1eve (Turkish)]] | ||
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| + | |||
| + | [[Category: Acetylcholinesterase]] | ||
| + | [[Category: Single protein]] | ||
| + | [[Category: Torpedo californica]] | ||
| + | [[Category: Kryger, G.]] | ||
| + | [[Category: Silman, I.]] | ||
| + | [[Category: Sussman, J.L.]] | ||
| + | [[Category: E20]] | ||
| + | [[Category: NAG]] | ||
| + | [[Category: alpha/beta hydrolase]] | ||
| + | [[Category: alzheimer's disease]] | ||
| + | [[Category: catalytic triad]] | ||
| + | [[Category: drug]] | ||
| + | [[Category: glycosylated protein]] | ||
| + | [[Category: neurotransmitter cleavage]] | ||
| + | [[Category: serine hydrolase]] | ||
| + | [[Category: RCSB PDB Molecule of the Month]] | ||
Revision as of 19:28, 19 December 2012
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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.
|
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 1 chain structure with sequence from Torpedo californica. The June 2004 RCSB PDB Molecule of the Month feature on Acetylcholinesterase by David S. Goodsell is 10.2210/rcsb_pdb/mom_2004_6. Full crystallographic information is available from OCA.
Additional Resources
For additional information, see: Alzheimer's Disease
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).
