22FF

Crystal structure of thioredoxin gluthathione reductase from Schistosoma japonicum with the U597C mutation in complex with auranofin

Summary for 22FF

• Entry DOI: 10.2210/pdb22ff/pdb
• Descriptor: thioredoxin-disulfide reductase (NADPH), FLAVIN-ADENINE DINUCLEOTIDE, GOLD ION, ... (4 entities in total)
• Functional Keywords: tgr, oxidoreductase
• Biological source: Schistosoma japonicum
• Total number of polymer chains: 2
• Total formula weight: 132981.00

Authors

Wang, S.Q.,Huang, S.Q.,Lin, T.W. (deposition date: 2026-01-08, release date: 2026-04-15, Last modification date: 2026-05-27)

Primary citation

Wang, S.,Hong, W.,Zhong, S.,Liang, Z.,Xiao, T.,Zhang, C.,Liu, X.,Dai, Z.,Li, Y.,Wu, S.,Cai, Q.,Wu, C.,Huang, Y.,Hong, P.,Ren, H.,Li, S.,Lin, T.,Chen, X.,Huang, S.
Structural basis for substrate recognition and inhibition of thioredoxin glutathione reductase from Schistosoma japonicum: Implications for antiparasitic development.
Plos Pathog., 22:e1014125-e1014125, 2026

PubMed Abstract: Praziquantel (PZQ) is currently the only agent for treating schistosomiasis, but it is plagued by suboptimal efficacy to juvenile parasites, looming drug resistance, and inability to prevent reinfection. Thioredoxin glutathione reductase (TGR) is regarded as a promising therapeutic target due to its essential role in maintaining schistosome redox homeostasis. Herein, the crystal structures of Schistosoma japonicum TGR (SjTGR) in multiple redox states and in complex with NADPH, GSH, and the anti-helminthic agent Auranofin were elucidated. Structural analyses identified the hook-shaped conformation at the C-terminal redox center, which DTNB assays further confirmed enhances electron transfer efficiency. Structural and ITC data indicated that R317 was critical for NADPH binding via hydrogen-bond interactions. The analysis also indicated that the structure basis of Auranofin's potency was its tripartite interaction at the redox-active sites. In addition, we investigated the substrate specificity of SjTrx1i and SjTRP14, downstream proteins regulated by SjTGR, and elucidated the structural basis for this specificity by determining their oxidized/reduced structures. Furthermore, in vivo RNAi indicated knockdown of SjTGR or SjTRP14 blocked the survival and oviposition of schistosomes, thus ameliorating egg-induced granulomatous pathology in mice. This work provided a framework for knowledge-based design of novel anti-schistosomals targeting parasite-specific redox vulnerabilities.

PubMed: 42030356
DOI: 10.1371/journal.ppat.1014125

Experimental method

X-RAY DIFFRACTION (1.84 Å)