9G92

Crystal structure of thioredoxin reductase from Cryptosporidium parvum in the "in" conformation

これはPDB形式変換不可エントリーです。

9G92 の概要

• エントリーDOI: 10.2210/pdb9g92/pdb
• 分子名称: Thioredoxin reductase, FLAVIN-ADENINE DINUCLEOTIDE, DIMETHYL SULFOXIDE, ... (5 entities in total)
• 機能のキーワード: reductase, flavoprotein
• 由来する生物種: Cryptosporidium parvum
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 114540.43

構造登録者

Gabriele, F.,Palerma, M.,Ardini, M.,Bogard, J.,Chen, X.M.,Williams, D.L.,Angelucci, F. (登録日: 2024-07-24, 公開日: 2025-05-07, 最終更新日: 2025-05-28)

主引用文献

Gabriele, F.,Bogard, J.A.,Palerma, M.,Ardini, M.,Byrne, M.E.,Chen, X.M.,Petukhov, P.A.,Ippoliti, R.,Angelucci, F.,Williams, D.L.
Targeting Apicomplexan Parasites: Structural and Functional Characterization of Cryptosporidium Thioredoxin Reductase as a Novel Drug Target.
Biochemistry, 64:2212-2225, 2025

PubMed Abstract: Cryptosporidiosis poses a significant health threat to young children and immunocompromised individuals due to the lack of effective therapies. Here, we demonstrate that the redox system is fundamentally different from their human host. Humans possess independent glutathione (GSH) and thioredoxin (Trx) pathways. lacks authentic glutathione reductase (GR), and we hypothesize that it most likely utilizes the Trx reductase (TrxR) plus Trx couple to maintain GSH in its reduced state. Given the central role of CpTrxR in the parasite's redox homeostasis, we focus on its functional and structural characterization. We find that the combination of CpTrxR and Trx efficiently reduces oxidized GSH, in effect functioning as a GR. Auranofin, a gold-containing compound, is known to kill parasites in culture, and here we demonstrate that CpTrxR is irreversibly inhibited by this compound. The crystallographic structures of CpTrxR, a type II TrxR characterized by the distinctive C-terminal -CGGGKCG motif found exclusively in apicomplexan parasites, including spp., the causative agents of malaria, are presented. Our study characterizes three unprecedented catalytically competent intermediates of the C-terminal tail in the so-called "in" conformations, providing insights into the structural and functional properties of type II TrxR. These findings offer valuable information for the design of CpTrxR inhibitors, addressing the pressing need for new therapeutic options against cryptosporidiosis, particularly in populations where current treatments are insufficiently effective.

PubMed: 40304242
DOI: 10.1021/acs.biochem.5c00059

実験手法

X-RAY DIFFRACTION (1.95 Å)