6XCC

Structure of the C. botulinum neurotoxin serotype A light chain protease in complex with covalent inhibitor 21

6XCC の概要

• エントリーDOI: 10.2210/pdb6xcc/pdb
• 分子名称: Botulinum neurotoxin type A, ZINC ION, N-hydroxy-5-sulfanylpentanamide, ... (4 entities in total)
• 機能のキーワード: covalent inhibitor, hydroxamate, toxin, toxin-inhibitor complex, toxin/inhibitor
• 由来する生物種: Clostridium botulinum
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 50669.50

構造登録者

Tararina, M.A.,Allen, K.N. (登録日: 2020-06-08, 公開日: 2020-09-23, 最終更新日: 2024-10-09)

主引用文献

Lin, L.,Olson, M.E.,Sugane, T.,Turner, L.D.,Tararina, M.A.,Nielsen, A.L.,Kurbanov, E.K.,Pellett, S.,Johnson, E.A.,Cohen, S.M.,Allen, K.N.,Janda, K.D.
Catch and Anchor Approach To Combat Both Toxicity and Longevity of Botulinum Toxin A.
J.Med.Chem., 63:11100-11120, 2020

PubMed Abstract: Botulinum neurotoxins have remarkable persistence (∼weeks to months in cells), outlasting the small-molecule inhibitors designed to target them. To address this disconnect, inhibitors bearing two pharmacophores-a zinc binding group and a Cys-reactive warhead-were designed to leverage both affinity and reactivity. A series of first-generation bifunctional inhibitors was achieved through structure-based inhibitor design. Through X-ray crystallography, engagement of both the catalytic Zn and Cys165 was confirmed. A second-generation series improved on affinity by incorporating known reversible inhibitor pharmacophores; the mechanism was confirmed by exhaustive dialysis, mass spectrometry, and evaluation against the C165S mutant. Finally, a third-generation inhibitor was shown to have good cellular activity and low toxicity. In addition to our findings, an alternative method of modeling time-dependent inhibition that simplifies assay setup and allows comparison of inhibition models is discussed.

PubMed: 32886509
DOI: 10.1021/acs.jmedchem.0c01006

実験手法

X-RAY DIFFRACTION (1.9 Å)