8CCU

Cathepsin B1 from Schistosoma mansoni in complex with gallinamide analog 1

これはPDB形式変換不可エントリーです。

8CCU の概要

• エントリーDOI: 10.2210/pdb8ccu/pdb
• 関連するPDBエントリー: 8CC2
• 分子名称: Cathepsin B-like peptidase (C01 family), [(2~{S})-1-[[(2~{S})-1-[[(2~{S})-5-[(2~{S})-3-methoxy-2-(2-methylpropyl)-5-oxidanylidene-2~{H}-pyrrol-1-yl]-5-oxidanylidene-pentan-2-yl]amino]-4-methyl-1-oxidanylidene-pentan-2-yl]amino]-4-methyl-1-oxidanylidene-pentan-2-yl] (2~{S},3~{S})-2-(dimethylamino)-3-methyl-pentanoate, SODIUM ION, ... (4 entities in total)
• 機能のキーワード: cysteine protease, cathepsin b, smcb1, schistosoma mansoni, protease inhibitor peptidomimetic, gallinamide a, 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: 29167.11

構造登録者

Rubesova, P.,Brynda, J.,Gerwick, W.H.,Mares, M. (登録日: 2023-01-27, 公開日: 2024-02-07, 最終更新日: 2024-10-23)

主引用文献

Spiwokova, P.,Horn, M.,Fanfrlik, J.,Jilkova, A.,Fajtova, P.,Leontovyc, A.,Houstecka, R.,Bielikova, L.,Brynda, J.,Chanova, M.,Mertlikova-Kaiserova, H.,Caro-Diaz, E.J.E.,Almaliti, J.,El-Sakkary, N.,Gerwick, W.H.,Caffrey, C.R.,Mares, M.
Nature-Inspired Gallinamides Are Potent Antischistosomal Agents: Inhibition of the Cathepsin B1 Protease Target and Binding Mode Analysis.
Acs Infect Dis., 10:1935-1948, 2024

PubMed Abstract: Schistosomiasis, caused by a parasitic blood fluke of the genus is a global health problem for which new chemotherapeutic options are needed. We explored the scaffold of gallinamide A, a natural peptidic metabolite of marine cyanobacteria that has previously been shown to inhibit cathepsin L-type proteases. We screened a library of 19 synthetic gallinamide A analogs and identified nanomolar inhibitors of the cathepsin B-type protease SmCB1, which is a drug target for the treatment of schistosomiasis mansoni. Against cultured schistosomula and adult worms, many of the gallinamides generated a range of deleterious phenotypic responses. Imaging with a fluorescent-activity-based probe derived from gallinamide A demonstrated that SmCB1 is the primary target for gallinamides in the parasite. Furthermore, we solved the high-resolution crystal structures of SmCB1 in complex with gallinamide A and its two analogs and describe the acrylamide covalent warhead and binding mode in the active site. Quantum chemical calculations evaluated the contribution of individual positions in the peptidomimetic scaffold to the inhibition of the target and demonstrated the importance of the P1' and P2 positions. Our study introduces gallinamides as a powerful chemotype that can be exploited for the development of novel antischistosomal chemotherapeutics.

PubMed: 38757505
DOI: 10.1021/acsinfecdis.3c00589

実験手法

X-RAY DIFFRACTION (1.6 Å)