3I06

Crystal structure of cruzain covalently bound to a purine nitrile

3I06 の概要

• エントリーDOI: 10.2210/pdb3i06/pdb
• 分子名称: Cruzipain, 6-[(3,5-difluorophenyl)amino]-9-ethyl-9H-purine-2-carbonitrile (3 entities in total)
• 機能のキーワード: autocatalytic cleavage, glycoprotein, protease, thiol protease, zymogen, hydrolase
• 由来する生物種: Trypanosoma cruzi
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 23015.40

構造登録者

Ferreira, R.S.,Shoichet, B.K.,McKerrow, J.H. (登録日: 2009-06-24, 公開日: 2009-12-15, 最終更新日: 2024-10-30)

主引用文献

Mott, B.T.,Ferreira, R.S.,Simeonov, A.,Jadhav, A.,Ang, K.K.,Leister, W.,Shen, M.,Silveira, J.T.,Doyle, P.S.,Arkin, M.R.,McKerrow, J.H.,Inglese, J.,Austin, C.P.,Thomas, C.J.,Shoichet, B.K.,Maloney, D.J.
Identification and optimization of inhibitors of trypanosomal cysteine proteases: cruzain, rhodesain, and TbCatB.
J.Med.Chem., 53:52-60, 2010

PubMed Abstract: Trypanosoma cruzi and Trypanosoma brucei are parasites that cause Chagas' disease and African sleeping sickness, respectively. Both parasites rely on essential cysteine proteases for survival: cruzain for T. cruzi and TbCatB/rhodesain for T. brucei. A recent quantitative high-throughput screen of cruzain identified triazine nitriles, which are known inhibitors of other cysteine proteases, as reversible inhibitors of the enzyme. Structural modifications detailed herein, including core scaffold modification from triazine to purine, improved the in vitro potency against both cruzain and rhodesain by 350-fold, while also gaining activity against T. brucei parasites. Selected compounds were screened against a panel of human cysteine and serine proteases to determine selectivity, and a cocrystal was obtained of our most potent analogue bound to cruzain.

PubMed: 19908842
DOI: 10.1021/jm901069a

実験手法

X-RAY DIFFRACTION (1.1 Å)