Journal
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
Volume 491, Issue 1-2, Pages 75-84Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.abb.2009.09.008
Keywords
Zinc protease; Inhibitor; Quinolinol; Peptide; Botulinum; Neurotoxin; Slow binding; Tight binding; Molecular modeling; Fluorescence titration
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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 K-D of 0.67 mu M and to Peptide C-BoNT/A LC complex with a K-D of 2.33 mu M. 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. (C) 2009 Elsevier Inc. All rights reserved.
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