8A1R

cryo-EM structure of thioredoxin glutathione reductase in complex with a non-competitive inhibitor

8A1R の概要

• エントリーDOI: 10.2210/pdb8a1r/pdb
• EMDBエントリー: 15084
• 分子名称: Thioredoxin glutathione reductase, FLAVIN-ADENINE DINUCLEOTIDE, (2~{R},3~{R},4~{S},5~{R})-2-[3-[[[(1~{R},2~{R},3~{R},5~{S})-2,6,6-trimethyl-3-bicyclo[3.1.1]heptanyl]amino]methyl]indol-1-yl]oxane-3,4,5-triol (3 entities in total)
• 機能のキーワード: inhibitor, complex, flavoreductase, flavoprotein
• 由来する生物種: Schistosoma mansoni
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 132522.47

構造登録者

Ardini, M.,Angelucci, F.,Fata, F.,Gabriele, F.,Effantin, G.,Ling, W.,Williams, D.L.,Petukhova, V.Z.,Petukhov, P.A. (登録日: 2022-06-01, 公開日: 2023-06-14, 最終更新日: 2024-11-13)

主引用文献

Petukhova, V.Z.,Aboagye, S.Y.,Ardini, M.,Lullo, R.P.,Fata, F.,Byrne, M.E.,Gabriele, F.,Martin, L.M.,Harding, L.N.M.,Gone, V.,Dangi, B.,Lantvit, D.D.,Nikolic, D.,Ippoliti, R.,Effantin, G.,Ling, W.L.,Johnson, J.J.,Thatcher, G.R.J.,Angelucci, F.,Williams, D.L.,Petukhov, P.A.
Non-covalent inhibitors of thioredoxin glutathione reductase with schistosomicidal activity in vivo.
Nat Commun, 14:3737-3737, 2023

PubMed Abstract: Only praziquantel is available for treating schistosomiasis, a disease affecting more than 200 million people. Praziquantel-resistant worms have been selected for in the lab and low cure rates from mass drug administration programs suggest that resistance is evolving in the field. Thioredoxin glutathione reductase (TGR) is essential for schistosome survival and a validated drug target. TGR inhibitors identified to date are irreversible and/or covalent inhibitors with unacceptable off-target effects. In this work, we identify noncovalent TGR inhibitors with efficacy against schistosome infections in mice, meeting the criteria for lead progression indicated by WHO. Comparisons with previous in vivo studies with praziquantel suggests that these inhibitors outperform the drug of choice for schistosomiasis against juvenile worms.

PubMed: 37349300
DOI: 10.1038/s41467-023-39444-y

実験手法

ELECTRON MICROSCOPY (3.6 Å)