5OGR

Structure of cathepsin B1 from Schistosoma mansoni in complex with WRR286 inhibitor

5OGR の概要

• エントリーDOI: 10.2210/pdb5ogr/pdb
• 関連するPDBエントリー: 3QSD 3S3Q 3S3R 4I04 4I05 4I07
• 分子名称: Cathepsin B-like peptidase (C01 family), 3-[[N-[4-METHYL-PIPERAZINYL]CARBONYL]-PHENYLALANINYL-AMINO]-5-PHENYL-PENTANE-1-SULFONIC ACID BENZYLOXY-AMIDE, ACETATE ION, ... (4 entities in total)
• 機能のキーワード: protease, parasite, inhibitor, vinyl sulfone, hydrolase
• 由来する生物種: Schistosoma mansoni (Blood fluke)
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 87564.27

構造登録者

Jilkova, A.,Rezacova, P.,Brynda, J.,Mares, M. (登録日: 2017-07-13, 公開日: 2018-11-21, 最終更新日: 2024-11-06)

主引用文献

Jilkova, A.,Rubesova, P.,Fanfrlik, J.,Fajtova, P.,Rezacova, P.,Brynda, J.,Lepsik, M.,Mertlikova-Kaiserova, H.,Emal, C.D.,Renslo, A.R.,Roush, W.R.,Horn, M.,Caffrey, C.R.,Mares, M.
Druggable Hot Spots in the Schistosomiasis Cathepsin B1 Target Identified by Functional and Binding Mode Analysis of Potent Vinyl Sulfone Inhibitors.
Acs Infect Dis., 2020

PubMed Abstract: Schistosomiasis, a parasitic disease caused by blood flukes of the genus , is a global health problem with over 200 million people infected. Treatment relies on just one drug, and new chemotherapies are needed. cathepsin B1 (SmCB1) is a critical peptidase for the digestion of host blood proteins and a validated drug target. We screened a library of peptidomimetic vinyl sulfones against SmCB1 and identified the most potent SmCB1 inhibitors reported to date that are active in the subnanomolar range with second order rate constants () of ∼2 × 10 M s. High resolution crystal structures of the two best inhibitors in complex with SmCB1 were determined. Quantum chemical calculations of their respective binding modes identified critical hot spot interactions in the S1' and S2 subsites. The most potent inhibitor targets the S1' subsite with an -hydroxysulfonic amide moiety and displays favorable functional properties, including bioactivity against the pathogen, selectivity for SmCB1 over human cathepsin B, and reasonable metabolic stability. Our results provide structural insights for the rational design of next-generation SmCB1 inhibitors as potential drugs to treat schistosomiasis.

PubMed: 33175511
DOI: 10.1021/acsinfecdis.0c00501

実験手法

X-RAY DIFFRACTION (1.55 Å)