2ZZB

Crystal structure of human thioredoxin reductase I and terpyridine platinum(II)

2ZZB の概要

• エントリーDOI: 10.2210/pdb2zzb/pdb
• 関連するPDBエントリー: 2ZZ0 2ZZC
• 分子名称: Thioredoxin reductase 1, cytoplasmic, FLAVIN-ADENINE DINUCLEOTIDE, SULFATE ION, ... (5 entities in total)
• 機能のキーワード: rossmann fold, alternative splicing, cytoplasm, electron transport, fad, flavoprotein, nadp, nucleus, oxidoreductase, phosphoprotein, polymorphism, redox-active center, selenium, selenocysteine, transport
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cytoplasm . Isoform 4: Cytoplasm. Isoform 5: Cytoplasm: Q16881
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 230415.36

構造登録者

Lo, Y.C.,Ko, T.P.,Wang, A.H.J. (登録日: 2009-02-09, 公開日: 2009-08-18, 最終更新日: 2024-10-30)

主引用文献

Lo, Y.C.,Ko, T.P.,Su, W.C.,Su, T.L.,Wang, A.H.J.
Terpyridine-platinum(II) complexes are effective inhibitors of mammalian topoisomerases and human thioredoxin reductase 1.
J.Inorg.Biochem., 103:1082-1092, 2009

PubMed Abstract: Terpyridine-platinum(II) (TP-Pt(II)) complexes are known to possess DNA-intercalating activity and have been regarded as potential antitumor agents. However, their cytotoxic mechanism remains unclear. To investigate the possible mechanism, a series of TP-Pt(II) compounds were prepared and their biological activities assessed. The DNA binding activities of the aromatic thiolato[TP-Pt(II)] complexes were stronger than the aliphatic 2-hydroxylethanethiolato(2,2':6',2''-terpyridine)platinum(II) [TP(HET)]. TP-Pt(II) complexes inhibited topoisomerase IIalpha or topoisomerase I activity at IC(50) values of about 5 microM and 10-20 microM, respectively, whereas the human thioredoxin reductase 1 (hTrxR1) activity was inhibited with IC(50) values in the range of 58-78 nM. At the cellular level, they possessed cytotoxicity with IC(50) values between 7 and 19 microM against HeLa cells. Additionally, using X-ray crystallography and matrix-assisted laser desorption/ionization (MALDI) mass spectrometry, we elucidated that the TP-Pt(II) complexes inhibited hTrxR1 activity by blocking its C-terminal active-site selenocysteine. Therefore, TP-Pt(II) complexes possess inhibitory activities against multiple biological targets, and they may be further studied as anticancer agents.

PubMed: 19525010
DOI: 10.1016/j.jinorgbio.2009.05.006

実験手法

X-RAY DIFFRACTION (3.2 Å)