Structural Characterization of Three Novel Hydroxamate-Based Zinc Chelating Inhibitors of the Clostridium botulinum Serotype A Neurotoxin Light Chain Metalloprotease Reveals a Compact Binding S

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• 作者：Aaron A. Thompson ; Guan-Sheng Jiao ; Seongjin Kim ; April Thai ; Lynne Cregar-Hernandez ; Stephen A. Margosiak ; Alan T. Johnson ; Gye Won Han ; Sean O鈥橫alley ; Raymond C. Stevens
• 刊名：Biochemistry
• 出版年：2011
• 出版时间：May 17, 2011
• 年：2011
• 卷：50
• 期：19
• 页码：4019-4028
• 全文大小：1128K
• 年卷期：v.50,no.19(May 17, 2011)
• ISSN：1520-4995

文摘

Neurotoxins synthesized by Clostridium botulinum bacteria (BoNT), the etiological agent of human botulism, are extremely toxic proteins making them high-risk agents for bioterrorism. Small molecule inhibitor development has been focused on the light chain zinc-dependent metalloprotease domain of the neurotoxin, an effort that has been hampered by its relatively flexible active site. Developed in concert with structure鈭抋ctivity relationship studies, the X-ray crystal structures of the complex of BoNT serotype A light chain (BoNT/A LC) with three different micromolar-potency hydroxamate-based inhibitors are reported here. Comparison with an unliganded BoNT/A LC structure reveals significant changes in the active site as a result of binding by the unique inhibitor scaffolds. The 60/70 loop at the opening of the active site pocket undergoes the largest conformational change, presumably through an induced-fit mechanism, resulting in the most compact catalytic pocket observed in all known BoNT/A LC structures.