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| - | '''This page is a continuation of the page [[AChE bivalent inhibitors]]'''
| + | #REDIRECT [[AChE inhibitors and substrates]] |
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| - | <applet load='ACHE3.pdb' size='500' frame='true' align='right'
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| - | scene='1e3q/Cv/1' />
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| - | Similarly to the other AChE bivalent inhibitors, <font color='magenta'><b>BW284C51 (BW)</b></font> also binds the ''Tc''AChE ([[1e3q]]) at the both subsites: CAS and PAS of its <scene name='1e3q/Active_site/1'>active site</scene>. At the CAS, BW makes a cation-aromatic interaction via quaternary group with <scene name='1e3q/Active_site/2'>Trp84</scene> <font color='orange'><b>(colored orange)</b></font>, BW phenyl ring forms an aromatic-aromatic interaction with His440, there is also an electrostatic interaction between the BW proximal quaternary group and Glu199. Near the PAS, BW via its distal quaternary group interacts with <scene name='1e3q/Active_site/3'>Trp279</scene> <font color='cyan'><b>(colored cyan)</b></font> and forms an aromatic interaction with Tyr334. BW forms hydrogen bond with Tyr121 OH, and makes alkyl interactions with Phe331. The superposition of BW with two other AChE bivalent inhibitors <scene name='1e3q/Active_site/4'>DECA</scene> <font color='gray'><b>(decamethonium, colored gray, [[1acl]])</b></font> and <scene name='1e3q/Active_site/5'>E2020</scene> <font color='blueviolet'><b>(Aricept, colored blueviolet, [[1eve]])</b></font> at the ''Tc''AChE active site reveals similar mode of binding. All these 3 inhibitors form cation-π and π-π interactions with active-site gorge aromatic residues <scene name='1e3q/Active_site/6'>(Tyr70, Trp84, Trp279 and Phe330 or Tyr334)</scene> <font color='yellow'><b>(colored yellow)</b></font>. The superposition of <scene name='1e3q/Active_site/7'>DECA and E2020</scene> reveals their similar position at the active site, but <scene name='1e3q/Active_site/8'>BW</scene> has a different trajectory from them. This causes the <scene name='1e3q/Active_site/9'>different conformation of Phe330</scene>, which interacts stronger with BW than with DECA and E2020. However, the conformations of the other important residues at the active site are similar in all these inhibitor-''Tc''AChE complexes.
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| - | It has been shown experimentally that BW and E2020 bind to ''Tc''AChE approximately 100-fold stronger than DECA. These findings could be explained by several reasons: ''i)'' E2020 and BW are less flexible than DECA; ''ii)'' the aromatic groups of E2020 and BW form favourable π-π interactions with ''Tc''AChE aromatic residues, in contrast to DECA; and ''iii)'' <scene name='1e3q/Shape/3'>BW</scene> and <scene name='1e3q/Shape/2'>E2020</scene> have aromatic groups and, therefore, occupy more volume and better fit the active-site gorge, than <scene name='1e3q/Shape/4'>string-shaped DECA</scene>. Mutations at the mouse or chicken AChE residues, corresponding to the ''Tc''AChE <scene name='1e3q/Active_site/10'>Tyr70, Trp84, Trp279 and Tyr121</scene> <font color='red'><b>(colored red)</b></font>, cause significant increase of inhibition constant values for all these 3 inhibitors, supporting the notion that these residues are critical for inhibitor-AChE binding.
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| - | ==Reference==
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| - | Structure of a complex of the potent and specific inhibitor BW284C51 with Torpedo californica acetylcholinesterase., Felder CE, Harel M, Silman I, Sussman JL, Acta Crystallogr D Biol Crystallogr. 2002 Oct;58(Pt 10 Pt 2):1765-71. Epub, 2002 Sep 28. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/12351819 12351819]
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Current revision
- REDIRECT AChE inhibitors and substrates
