Aricept Complexed with Acetylcholinesterase (Spanish)
From Proteopedia
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==Resultados== | ==Resultados== | ||
The X-ray structure of the E2020-''Tc''AChE complex shows that E2020 has a <scene name='1eve/E2020_close_up_with_84_279/10'>unique orientation</scene> along the active-site gorge, extending from the anionic subsite (<scene name='1eve/E2020_close_up_with_84lbld/5'>W84</scene>) of the active site, at the bottom, to the peripheral anionic site (<scene name='1eve/E2020_close_up_with_84_279lbld/4'>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/7'>indirectly via solvent molecules</scene>. | The X-ray structure of the E2020-''Tc''AChE complex shows that E2020 has a <scene name='1eve/E2020_close_up_with_84_279/10'>unique orientation</scene> along the active-site gorge, extending from the anionic subsite (<scene name='1eve/E2020_close_up_with_84lbld/5'>W84</scene>) of the active site, at the bottom, to the peripheral anionic site (<scene name='1eve/E2020_close_up_with_84_279lbld/4'>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/7'>indirectly via solvent molecules</scene>. | ||
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| + | La estructura de rayos X del complejo E2020-''Tc''AChE pone de manifiesto que el E2020 tiene una <scene name='1eve/E2020_close_up_with_84_279/10'>orientacion unica</scene> a lo largo del ''gorge'' del sitio activo, extendiendose desde el sub-sitio anionico (<scene name='1eve/E2020_close_up_with_84lbld/5'>W84</scene>) del sitio activo, abajo, hacia el sitio periferico anionico (<scene name='1eve/E2020_close_up_with_84_279lbld/4'>cerca W279</scene>), arriba, | ||
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| + | E2020, sin embargo, no interactua directamente con la triada catalitica ni con el 'huco oxyanion', solamente <scene name='1eve/E20_interactionshown/7'>en forma indirecta via moleculas solventes</scene>. | ||
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==Conclusiones== | ==Conclusiones== | ||
Revision as of 12:53, 3 August 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 | ||||||||
Estructura tridimensional de la droga contra la enfermedad de Alzheimer, Aricept, complejada con acetilcolinesterasa
(vea tambien Inhibidores bivalentes de AChE, Parte II)
Contents |
Antecedentes
Varios inhibidores de la colinesterasa se utilizan para el tratamiento sintomático de la enfermedad de Alzheimer o se encuentran en estado avanzado de ensayo clínico. E2020, comercializado como Aricept, es miembro de una familia numerosa de la N-benzylpiperidine basada en inhibidores de la acetilcholinesterasa (AChE), desarrollado, sintetizado y evaluado por la Compañía Eisai en el Japón. Estos inhibidores fueron diseñados sobre la base de estudios QSAR, antes de conocerse la estructura 3D de la AChE de Torpedo californica (TcAChE) (1ea5). Con este inhibidor se mejora significativamente el rendimiento en animales de hipofunción colinérgica y tiene una alta afinidad por la AChE, vinculante para anguila eléctrica y el ratón en el rango nanomolar de AChE.
Resultados
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 .
La estructura de rayos X del complejo E2020-TcAChE pone de manifiesto que el E2020 tiene una a lo largo del gorge del sitio activo, extendiendose desde el sub-sitio anionico () del sitio activo, abajo, hacia el sitio periferico anionico (), arriba,
E2020, sin embargo, no interactua directamente con la triada catalitica ni con el 'huco oxyanion', solamente .
Conclusiones
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.
Acerca de esta Estructura
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.
Referencias
- Kryger G, Silman I, Sussman JL. Structure of acetylcholinesterase complexed with E2020 (Aricept): implications for the design of new anti-Alzheimer drugs. Structure. 1999 Mar 15;7(3):297-307. PMID:10368299
- See 1eve (Chinese).
Proteopedia Page Contributors and Editors (what is this?)
Jaime Prilusky, Joel L. Sussman, Fred Vellieux, Alexander Berchansky, Angel Herraez
