2ILP

Clostridium botulinum Serotype A Light Chain inhibited by 4-chlorocinnamic hydroxamate

2ILP の概要

• エントリーDOI: 10.2210/pdb2ilp/pdb
• 分子名称: Botulinum neurotoxin A light-chain, ZINC ION, PHOSPHATE ION, ... (5 entities in total)
• 機能のキーワード: clostridium botulinum neurotoxin, type a, substrate specificity, substrate switching, protease inhibitors, hydrolase
• 由来する生物種: Clostridium botulinum
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 102255.57

構造登録者

Silvaggi, N.R.,Allen, K.N. (登録日: 2006-10-03, 公開日: 2007-06-05, 最終更新日: 2024-02-21)

主引用文献

Silvaggi, N.R.,Boldt, G.E.,Hixon, M.S.,Kennedy, J.P.,Tzipori, S.,Janda, K.D.,Allen, K.N.
Structures of Clostridium botulinum Neurotoxin Serotype A Light Chain Complexed with Small-Molecule Inhibitors Highlight Active-Site Flexibility.
Chem.Biol., 14:533-542, 2007

PubMed Abstract: 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.

PubMed: 17524984
DOI: 10.1016/j.chembiol.2007.03.014

実験手法

X-RAY DIFFRACTION (1.9 Å)