C-Terminus of Botulinum A Protease Has Profound and Unanticipated Kinetic Consequences upon the Catalytic Cleft

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• 作者：Peter 艩ilh谩r ; Matthew A. Lardy ; Mark S. Hixon ; Charles B. Shoemaker ; Joseph T. Barbieri ; Anjali K. Struss ; Jenny M. Lively ; Sacha Javor ; Kim D. Janda
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2013
• 出版时间：February 14, 2013
• 年：2013
• 卷：4
• 期：2
• 页码：283-287
• 全文大小：273K
• 年卷期：v.4,no.2(February 14, 2013)
• ISSN：1948-5875

文摘

Botulinum neurotoxins (BoNTs) are among the most deadly poisons known, though ironically, they also are of great therapeutic utility. A number of research programs have been initiated to discover small molecule inhibitors of BoNTs metalloprotease activity. Many, though not all, of these programs have screened against a truncated and more stable form of the enzyme, that possesses comparable catalytic properties to the full length enzyme. Interestingly, several classes of inhibitors, notably the hydroxamates, display a large shift in potency between the two enzyme forms. In this report we compare the kinetics of active-site, 伪-exosite and 尾-exosite inhibitors versus truncated and full length enzyme. Molecular dynamics simulations conducted with the truncated and homology models of the full length BoNT LC/A indicate the flexibility of the C-terminus of the full length enzyme is responsible for the potency shifts of active-site proximally binding inhibitors while distal binding (伪-exosite) inhibitors remain equipotent.

Keywords:

Botulinum neurotoxin; zinc-dependent metalloprotease; protease inhibitor; small molecule inhibitor; natural product