Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
1926255 | Archives of Biochemistry and Biophysics | 2009 | 10 Pages |
Abstract
Quinolinol derivatives were found to be effective inhibitors of botulinum neurotoxin serotype A (BoNT/A). Studies of the inhibition and binding of 7-(phenyl(8-quinolinylamino)methyl)-8-quinolinol (QAQ) to the light chain domain (BoNT/A LC) showed that QAQ is a non-competitive inhibitor for the zinc protease activity. Binding and molecular modeling studies reveal that QAQ binds to a hydrophobic pocket near the active site. Its inhibitor effect does not involve the removal of zinc ion from the light chain. A 24-mer SNAP-25 peptide containing E183 to G206 with Q197C mutation (Peptide C) binds to BoNT/A LC with an unusually slow second order binding rate constant of 76.7 Mâ1 sâ1. QAQ binds to Zn2+-free BoNT/A LC with a KD of 0.67 μM and to Peptide C-BoNT/A LC complex with a KD of 2.33 μM. The insights of the interactions of quinolinols and peptides with the zinc protease of BoNT/A should aid in the development of inhibitors of metalloproteases.
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Authors
Huiguo Lai, Minghao Feng, Virginia Roxas-Duncan, Sivanesan Dakshanamurthy, Leonard A. Smith, David C.H. Yang,