Journal:Protein Science:1
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The photosensitizer, <scene name='Journal:Protein_Science:1/Cv/3'>methylene blue (MB)</scene>, generates singlet oxygen that irreversibly inhibits Torpedo californica acetylcholinesterase (''Tc''AChE). In the dark, it inhibits reversibly. | The photosensitizer, <scene name='Journal:Protein_Science:1/Cv/3'>methylene blue (MB)</scene>, generates singlet oxygen that irreversibly inhibits Torpedo californica acetylcholinesterase (''Tc''AChE). In the dark, it inhibits reversibly. | ||
The ''Tc''AChE active site consists of two binding subsites. One of them is the '''"catalytic anionic site" (CAS)''', which involves the catalytic triad <scene name='Journal:Protein_Science:1/Cv/6'>Ser200, His440, and Glu327</scene> <font color='orange'><b>(colored orange)</b></font> and the conserved residues <scene name='Journal:Protein_Science:1/Cv/8'>Trp84 and Phe330</scene> which also participate in ligand recognition. Another conserved residue <scene name='Journal:Protein_Science:1/Cv/9'>Trp279</scene> <font color='cyan'><b>(colored cyan)</b></font> is situated at the second binding subsite, termed the '''"peripheral anionic site" (PAS)''', ~14 Å from CAS. <scene name='Journal:Protein_Science:1/Cv/10'>Thioflavin T</scene> ([[2j3q]]) is a good example of the '''PAS-binding''' AChE inhibitors. <scene name='Journal:Protein_Science:1/Cv/11'>Superposition</scene> of the structure of known '''CAS-binding''' inhibitor <font color='crimson'><b>edrophonium</b></font>/''Tc''AChE ([[2ack]]) on the <font color='magenta'><b>thioflavin T</b></font>/''Tc''AChE complex structure ([[2j3q]]) shows that these <scene name='Journal:Protein_Science:1/Cv/12'>ligands' positions do not overlap</scene><ref name="Ravelli">PMID:10089512</ref> <ref name="Sonoda">PMID:18512913</ref>. | The ''Tc''AChE active site consists of two binding subsites. One of them is the '''"catalytic anionic site" (CAS)''', which involves the catalytic triad <scene name='Journal:Protein_Science:1/Cv/6'>Ser200, His440, and Glu327</scene> <font color='orange'><b>(colored orange)</b></font> and the conserved residues <scene name='Journal:Protein_Science:1/Cv/8'>Trp84 and Phe330</scene> which also participate in ligand recognition. Another conserved residue <scene name='Journal:Protein_Science:1/Cv/9'>Trp279</scene> <font color='cyan'><b>(colored cyan)</b></font> is situated at the second binding subsite, termed the '''"peripheral anionic site" (PAS)''', ~14 Å from CAS. <scene name='Journal:Protein_Science:1/Cv/10'>Thioflavin T</scene> ([[2j3q]]) is a good example of the '''PAS-binding''' AChE inhibitors. <scene name='Journal:Protein_Science:1/Cv/11'>Superposition</scene> of the structure of known '''CAS-binding''' inhibitor <font color='crimson'><b>edrophonium</b></font>/''Tc''AChE ([[2ack]]) on the <font color='magenta'><b>thioflavin T</b></font>/''Tc''AChE complex structure ([[2j3q]]) shows that these <scene name='Journal:Protein_Science:1/Cv/12'>ligands' positions do not overlap</scene><ref name="Ravelli">PMID:10089512</ref> <ref name="Sonoda">PMID:18512913</ref>. | ||
| - | MB is a noncompetitive inhibitor of ''Tc''AChE, competing with reversible inhibitors directed at both ‘‘anionic’’ subsites, but a single site is involved in inhibition. The crystal structure reveals a <scene name='Journal:Protein_Science:1/Cv1/2'>single MB stacked against Trp279 in the PAS</scene>, oriented down the gorge toward the CAS; it is plausible that irreversible inhibition is associated with photooxidation of this residue and others within the active-site gorge. | + | MB is a noncompetitive inhibitor of ''Tc''AChE, competing with reversible inhibitors directed at both ‘‘anionic’’ subsites, but a single site is involved in inhibition. The crystal structure reveals a <scene name='Journal:Protein_Science:1/Cv1/2'>single MB stacked against Trp279 in the PAS</scene>, oriented down the gorge toward the CAS ([[2w9i]]); it is plausible that irreversible inhibition is associated with photooxidation of this residue and others within the active-site gorge. |
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Revision as of 10:55, 24 June 2012
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This page complements a publication in scientific journals and is one of the Proteopedia's Interactive 3D Complement pages. For aditional details please see I3DC.
