Au4 cluster inhibits human thioredoxin reductase activity via specifically binding of Au to Cys189

doi:10.1016/j.nantod.2022.101686

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	Au4 cluster inhibits human thioredoxin reductase activity via specifically binding of Au to Cys189
	Du, ZY; He, ZS; Fan, JD; Huo, YA; He, B; Wang, YR; Sun, QQ; Niu, WC; Zhao, WC; Zhao, LA; Cao, P; Cao, K; Xia, DF; Yuan, Q; Liang, XJ; Jiang, HD; Gong, Y; Gao, XY
	2022
发表期刊	NANO TODAY (IF:17.476[JCR-2016],19.234[5-Year])
ISSN	1748-0132
EISSN	1878-044X
卷号	47 页码:101686
条目编号	IHEP00035415
文章类型	Article
摘要	Studies have shown that Au triggers tumor cell apoptosis by directly inhibiting human thioredoxin re-ductase (hTrxR), thus making Au potential drugs for cancer treatment. However, the exact molecular me-chanism of Au inhibiting hTrxR has never been demonstrated via experimental and theoretical studies. Here, we synthesized an Au4 cluster coated by an artificial RGD peptide. This gold cluster can bind with hTrxR (KD: & SIM;1.74 mu M) in vitro, and significantly inhibit hTrxR activity in tumor cells. To analyze the un-derlying mechanism, we established hTrxR-overexpressing tumor cells and fished Au-hTrxR adducts from tumor cells previously treated by Au clusters. Using single-particle cryo-electron microscopy (Cryo-EM) and mass spectra (MS), we found unexpectedly that, Au (I) ion, metabolism of Au cluster, specifically binds to the Cys189 of hTrxR. Molecular dynamic simulation revealed such specific Au-Cys189 binding effectively broke the electron transfer from Sec498 of hTrxR to Cys32 of thioredoxin. This inhibition of hTrxR activity by Au4 cluster induced ROS-regulated tumor cell apoptosis and significantly suppressed tumor growth in an A549 lung cancer xenograft model. In summary, this study revealed the structural mechanism of Au in-hibiting hTrxR activity and shed light to the design and application of novel hTrxR-inhibitory anti-tumor nanodrugs.(c) 2022 Elsevier Ltd. All rights reserved.
关键词	Human thioredoxin reductase Thioredoxin Au cluster Anti-tumor nanodrug
DOI	10.1016/j.nantod.2022.101686
语种	英语
WOS记录号	WOS:000896014900001
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://ir.ihep.ac.cn/handle/311005/299926
专题	多学科研究中心粒子天体物理中心
作者单位	中国科学院高能物理研究所
第一作者单位	中国科学院高能物理研究所
推荐引用方式 GB/T 7714	Du, ZY,He, ZS,Fan, JD,et al. Au4 cluster inhibits human thioredoxin reductase activity via specifically binding of Au to Cys189[J]. NANO TODAY,2022,47:101686.
APA	Du, ZY.,He, ZS.,Fan, JD.,Huo, YA.,He, B.,...&Gao, XY.(2022).Au4 cluster inhibits human thioredoxin reductase activity via specifically binding of Au to Cys189.NANO TODAY,47,101686.
MLA	Du, ZY,et al."Au4 cluster inhibits human thioredoxin reductase activity via specifically binding of Au to Cys189".NANO TODAY 47(2022):101686.