7N18

Clostridium botulinum Neurotoxin Serotype A Light Chain Inhibited by a Chiral Hydroxamic Acid

7N18 の概要

• エントリーDOI: 10.2210/pdb7n18/pdb
• 分子名称: Botulinum neurotoxin type A, ZINC ION, (3R)-3-(4-chlorophenyl)-N,5-dihydroxypentanamide, ... (5 entities in total)
• 機能のキーワード: botulinum protease, bont/a, inhibitor, hydrolase, hydrolase-inhibitor complex, hydrolase/inhibitor
• 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: 102549.05

構造登録者

Silvaggi, N.R.,Allen, K.N. (登録日: 2021-05-27, 公開日: 2022-07-06, 最終更新日: 2024-01-17)

主引用文献

Turner, L.D.,Nielsen, A.L.,Lin, L.,Campedelli, A.J.,Silvaggi, N.R.,Chen, J.S.,Wakefield, A.E.,Allen, K.N.,Janda, K.D.
Use of Crystallography and Molecular Modeling for the Inhibition of the Botulinum Neurotoxin A Protease.
Acs Med.Chem.Lett., 12:1318-1324, 2021

PubMed Abstract: Botulinum neurotoxins (BoNTs) are extremely toxic and have been deemed a Tier 1 potential bioterrorism agent. The most potent and persistent of the BoNTs is the "A" serotype, with strategies to counter its etiology focused on designing small-molecule inhibitors of its light chain (LC), a zinc-dependent metalloprotease. The successful structure-based drug design of inhibitors has been confounded as the LC is highly flexible with significant morphological changes occurring upon inhibitor binding. To achieve greater success, previous and new cocrystal structures were evaluated from the standpoint of inhibitor enantioselectivity and their effect on active-site morphology. Based upon these structural insights, we designed inhibitors that were predicted to take advantage of π-π stacking interactions present in a cryptic hydrophobic subpocket. Structure-activity relationships were defined, and X-ray crystal structures and docking models were examined to rationalize the observed potency differences between inhibitors.

PubMed: 34413962
DOI: 10.1021/acsmedchemlett.1c00325

実験手法

X-RAY DIFFRACTION (2.03 Å)