Structures of Clostridium botulinum Neurotoxin Serotype A Light Chain complexed with small-molecule inhibitors highlight active-site flexibility. Chem Biol 2007 May;14(5):533-42
Date
05/26/2007Pubmed ID
17524984DOI
10.1016/j.chembiol.2007.03.014Scopus ID
2-s2.0-34248594822 (requires institutional sign-in at Scopus site) 116 CitationsAbstract
The potential for the use of Clostridial neurotoxins as bioweapons makes the development of small-molecule inhibitors of these deadly toxins a top priority. Recently, screening of a random hydroxamate library identified a small-molecule inhibitor of C. botulinum Neurotoxin Serotype A Light Chain (BoNT/A-LC), 4-chlorocinnamic hydroxamate, a derivative of which has been shown to have in vivo efficacy in mice and no toxicity. We describe the X-ray crystal structures of BoNT/A-LC in complexes with two potent small-molecule inhibitors. The structures of the enzyme with 4-chlorocinnamic hydroxamate or 2,4-dichlorocinnamic hydroxamate bound are compared to the structure of the enzyme complexed with L-arginine hydroxamate, an inhibitor with modest affinity. Taken together, this suite of structures provides surprising insights into the BoNT/A-LC active site, including unexpected conformational flexibility at the S1' site that changes the electrostatic environment of the binding pocket. Information gained from these structures will inform the design and optimization of more effective small-molecule inhibitors of BoNT/A-LC.
Author List
Silvaggi NR, Boldt GE, Hixon MS, Kennedy JP, Tzipori S, Janda KD, Allen KNAuthor
Nicholas R. Silvaggi PhD Assistant Professor in the Chemistry and Biochemistry department at University of Wisconsin - MilwaukeeMESH terms used to index this publication - Major topics in bold
AntitoxinsBacterial Toxins
Binding Sites
Chromatography, Liquid
Cloning, Molecular
Clostridium botulinum type A
Crystallography, X-Ray
DNA, Complementary
Glycosides
Models, Molecular
Models, Statistical
Molecular Conformation
Triterpenes
