Article ID Journal Published Year Pages File Type
1926255 Archives of Biochemistry and Biophysics 2009 10 Pages PDF
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 M−1 s−1. 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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