3QJ0

Crystal Structure of BoNT/A LC complexed with Hydroxamate-based Inhibitor PT-3

3QJ0 の概要

• エントリーDOI: 10.2210/pdb3qj0/pdb
• 関連するPDBエントリー: 3QIX 3QIY 3QIZ
• 分子名称: Botulinum neurotoxin type A, ZINC ION, (4R)-4-(4-chlorophenoxy)-1-[(4-chlorophenyl)sulfonyl]-N-hydroxy-L-prolinamide, ... (5 entities in total)
• 機能のキーワード: botulinum, bont, neurotoxin, toxin, hydroxamate, inhibitor, metalloprotease, protease, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Clostridium botulinum
• 細胞内の位置: Botulinum neurotoxin A light chain: Secreted. Botulinum neurotoxin A heavy chain: Secreted: A5HZZ9
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 50058.57

構造登録者

Thompson, A.A.,Han, G.W.,Stevens, R.C. (登録日: 2011-01-28, 公開日: 2011-04-13, 最終更新日: 2023-09-13)

主引用文献

Thompson, A.A.,Jiao, G.S.,Kim, S.,Thai, A.,Cregar-Hernandez, L.,Margosiak, S.A.,Johnson, A.T.,Han, G.W.,O'Malley, S.,Stevens, R.C.
Structural Characterization of Three Novel Hydroxamate-Based Zinc Chelating Inhibitors of the Clostridium botulinum Serotype A Neurotoxin Light Chain Metalloprotease Reveals a Compact Binding Site Resulting from 60/70 Loop Flexibility.
Biochemistry, 50:4019-4028, 2011

PubMed Abstract: 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--activity 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.

PubMed: 21434688
DOI: 10.1021/bi2001483

実験手法

X-RAY DIFFRACTION (2.301 Å)