6YI7

Structure of cathepsin B1 from Schistosoma mansoni (SmCB1) in complex with an azanitrile inhibitor

6YI7 の概要

• エントリーDOI: 10.2210/pdb6yi7/pdb
• 関連するPDBエントリー: 3QSD 3S3Q 3S3R 4I04 4I05 4I07 5OGQ 5OGR
• 分子名称: Cathepsin B-like peptidase (C01 family), ACETATE ION, 1-[(2~{S})-1-[[iminomethyl(methyl)amino]-methyl-amino]-4-methyl-1-oxidanylidene-pentan-2-yl]-3-(phenylmethyl)urea, ... (4 entities in total)
• 機能のキーワード: cysteine protease, parasite, inhibitor, azanitrile, hydrolase
• 由来する生物種: Schistosoma mansoni
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 28958.77

構造登録者

Jilkova, A.,Rezacova, P.,Pachl, P.,Fanfrlik, J.,Rubesova, P.,Guetschow, M.,Mares, M. (登録日: 2020-04-01, 公開日: 2020-12-16, 最終更新日: 2024-11-06)

主引用文献

Jilkova, A.,Horn, M.,Fanfrlik, J.,Kuppers, J.,Pachl, P.,Rezacova, P.,Lepsik, M.,Fajtova, P.,Rubesova, P.,Chanova, M.,Caffrey, C.R.,Gutschow, M.,Mares, M.
Azanitrile Inhibitors of the SmCB1 Protease Target Are Lethal to Schistosoma mansoni : Structural and Mechanistic Insights into Chemotype Reactivity.
Acs Infect Dis., 7:189-201, 2021

PubMed Abstract: Azapeptide nitriles are postulated to reversibly covalently react with the active-site cysteine residue of cysteine proteases and form isothiosemicarbazide adducts. We investigated the interaction of azadipeptide nitriles with the cathepsin B1 drug target (SmCB1) from , a pathogen that causes the global neglected disease schistosomiasis. Azadipeptide nitriles were superior inhibitors of SmCB1 over their parent carba analogs. We determined the crystal structure of SmCB1 in complex with an azadipeptide nitrile and analyzed the reaction mechanism using quantum chemical calculations. The data demonstrate that azadipeptide nitriles, in contrast to their carba counterparts, undergo a change from - to -configuration upon binding, which gives rise to a highly favorable energy profile of noncovalent and covalent complex formation. Finally, azadipeptide nitriles were considerably more lethal than their carba analogs against the schistosome pathogen in culture, supporting the further development of this chemotype as a treatment for schistosomiasis.

PubMed: 33301315
DOI: 10.1021/acsinfecdis.0c00644

実験手法

X-RAY DIFFRACTION (1.29 Å)