Botulinum Neurotoxin A Protease: Discovery of Natural Product Exosite Inhibitors
نویسندگان
چکیده
منابع مشابه
Structural insight into exosite binding and discovery of novel exosite inhibitors of botulinum neurotoxin serotype A through in silico screening
Botulinum neurotoxin serotype A (BoNT/A) is the most lethal toxin among the Tier 1 Select Agents. Development of potent and selective small molecule inhibitors against BoNT/A zinc metalloprotease remains a challenging problem due to its exceptionally large substrate binding surface and conformational plasticity. The exosites of the catalytic domain of BoNT/A are intriguing alternative sites for...
متن کاملA cross-over inhibitor of the botulinum neurotoxin light chain B: a natural product implicating an exosite mechanism of action.
Clostridium botulinum produces the most lethal toxins known to man, as such they are high risk terrorist threats, and alarmingly there is no approved therapeutic. We report the first cross-over small molecule inhibitor of these neurotoxins and propose a mechanism by which it may impart its inhibitory activity.
متن کاملTyrosine Phosphorylation of Botulinum Neurotoxin Protease Domains
Botulinum neurotoxins are most potent of all toxins. Their N-terminal light chain domain (Lc) translocates into peripheral cholinergic neurons to exert its endoproteolytic action leading to muscle paralysis. Therapeutic development against these toxins is a major challenge due to their in vitro and in vivo structural differences. Although three-dimensional structures and reaction mechanisms are...
متن کاملToward the discovery of dual inhibitors for botulinum neurotoxin A: concomitant targeting of endocytosis and light chain protease activity.
Dyngo-4a™ has been found to be an endocytic inhibitor of BoNT/A neurotoxicity through dynamin inhibition. Herein, we demonstrate this molecule to have a previously unrecognized dual activity against BoNT/A, dynamin-protease inhibition. To establish the importance of this dual activity, detailed kinetic analysis of Dyngo-4a's inhibition of BoNT/A metalloprotease as well as cellular and animal to...
متن کاملRole of a protease in natural activation of Clostridium botulinum neurotoxin.
All tested proteolytic Clostridium botulinum type A, B, and F strains and certain non-proteolytic B and F cultures produced a protease having trypsin-like substrate specificity; none of the tested type E (non-proteolytic) strains produced the enzyme. Progenitor toxin (toxic form whose specific toxicity is increased by treatment with trypsin) was found in culture fluid concentrates of all strain...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
ژورنال
عنوان ژورنال: Journal of the American Chemical Society
سال: 2010
ISSN: 0002-7863,1520-5126
DOI: 10.1021/ja910761y