7PUT

Crystal structure of Thioredoxin Reductase from Brugia Malayi in complex with NADP(H)

7PUT の概要

• エントリーDOI: 10.2210/pdb7put/pdb
• 分子名称: Glutaredoxin domain-containing protein, FLAVIN-ADENINE DINUCLEOTIDE, (4S)-2-METHYL-2,4-PENTANEDIOL, ... (6 entities in total)
• 機能のキーワード: glutaredoxin, flavoprotein, selenocysteine, oxidoreductase
• 由来する生物種: Brugia malayi (Filarial nematode worm); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 202015.39

構造登録者

Fata, F.,Ardini, M.,Silvestri, I.,Gabriele, F.,Ippoliti, R.,Gencheva, R.,Cheng, Q.,Arner, E.S.J.,Angelucci, F.,Williams, D.L. (登録日: 2021-09-30, 公開日: 2022-04-06, 最終更新日: 2024-11-13)

主引用文献

Fata, F.,Gencheva, R.,Cheng, Q.,Lullo, R.,Ardini, M.,Silvestri, I.,Gabriele, F.,Ippoliti, R.,Bulman, C.A.,Sakanari, J.A.,Williams, D.L.,Arner, E.S.J.,Angelucci, F.
Biochemical and structural characterizations of thioredoxin reductase selenoproteins of the parasitic filarial nematodes Brugia malayi and Onchocerca volvulus.
Redox Biol, 51:102278-102278, 2022

PubMed Abstract: Enzymes in the thiol redox systems of microbial pathogens are promising targets for drug development. In this study we characterized the thioredoxin reductase (TrxR) selenoproteins from Brugia malayi and Onchocerca volvulus, filarial nematode parasites and causative agents of lymphatic filariasis and onchocerciasis, respectively. The two filarial enzymes showed similar turnover numbers and affinities for different thioredoxin (Trx) proteins, but with a clear preference for the autologous Trx. Human TrxR1 (hTrxR1) had a high and similar specific activity versus the human and filarial Trxs, suggesting that, in vivo, hTrxR1 could possibly be the reducing agent of parasite Trxs once they are released into the host. Both filarial TrxRs were efficiently inhibited by auranofin and by a recently described inhibitor of human TrxR1 (TRi-1), but not as efficiently by the alternative compound TRi-2. The enzyme from B. malayi was structurally characterized also in complex with NADPH and auranofin, producing the first crystallographic structure of a nematode TrxR. The protein represents an unusual fusion of a mammalian-type TrxR protein architecture with an N-terminal glutaredoxin-like (Grx) domain lacking typical Grx motifs. Unlike thioredoxin glutathione reductases (TGRs) found in platyhelminths and mammals, which are also Grx-TrxR domain fusion proteins, the TrxRs from the filarial nematodes lacked glutathione disulfide reductase and Grx activities. The structural determinations revealed that the Grx domain of TrxR from B. malayi contains a cysteine (C22), conserved in TrxRs from clade IIIc nematodes, that directly interacts with the C-terminal cysteine-selenocysteine motif of the homo-dimeric subunit. Interestingly, despite this finding we found that altering C22 by mutation to serine did not affect enzyme catalysis. Thus, although the function of the Grx domain in these filarial TrxRs remains to be determined, the results obtained provide insights on key properties of this important family of selenoprotein flavoenzymes that are potential drug targets for treatment of filariasis.

PubMed: 35276442
DOI: 10.1016/j.redox.2022.102278

実験手法

X-RAY DIFFRACTION (2.8 Å)