Salvicine functions as novel topoisomerase II poison by binding to ATP pocket

doi:10.1124/mol.106.027714

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药理学第一研究室

	Salvicine functions as novel topoisomerase II poison by binding to ATP pocket
	Hu, Chao-Xin ; Zuo, Zhi-Li ; Xiong, Bing; Ma, Jin-Gui ; Geng, Mei-Yu; Lin, Li-Ping ; Jiang, Hua-Liang; Ding, Jian
刊名	MOLECULAR PHARMACOLOGY
	2006-11
卷号	70 期号:5 页码:1593-1601
ISSN号	0026-895X
DOI	10.1124/mol.106.027714
文献子类	Article
英文摘要	Salvicine, a structurally modified diterpenoid quinone derived from Salvia prionitis, is a nonintercalative topoisomerase II (topo II) poison. The compound possesses potent in vitro and in vivo antitumor activity with a broad spectrum of anti-multidrug resistance activity and is currently in phase II clinical trials. To elucidate the distinct antitumor properties of salvicine and obtain valuable structural information of salvicine-topo II interactions, we characterized the effects of salvicine on human topo II alpha (htopo II alpha), including possible binding sites and molecular interactions. The enzymatic assays disclosed that salvicine mainly inhibits the catalytic activity with weak DNA cleavage action, in contrast to the classic topo II poison etoposide (VP16). Molecular modeling studies predicted that salvicine binds to the ATP pocket in the ATPase domain and superimposes on the phosphate and ribose groups. In a surface plasmon resonance binding assay, salvicine exhibited higher affinity for the ATPase domain of htopo II alpha than ATP and ADP. Competitive inhibition tests demonstrated that ATP competitively and dose-dependently blocked the interactions between salvicine and ATPase domain of htopo II alpha. The data illustrate that salvicine shares a common binding site with ATP and functions as an ATP competitor. To our knowledge, this is the first report to identify an ATP-binding pocket as the structural binding motif for a nonintercalative eukaryotic topo II poison. These findings collectively support the potential value of an ATP competitor of htopo II alpha in tumor chemotherapy.
WOS关键词	DNA TOPOISOMERASE ; PROTEIN CLAMP ; ENZYME ; DRUGS ; ALPHA ; INHIBITORS ; MECHANISM ; APOPTOSIS ; CLEAVAGE ; TARGET
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
WOS记录号	WOS:000241436100014
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/273461]
专题	药理学第一研究室中科院受体结构与功能重点实验室新药研究国家重点实验室
通讯作者	Ding, Jian
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery Design Ctr, State Key Lab Drug Res, Shanghai 201203, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumour Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Hu, Chao-Xin,Zuo, Zhi-Li,Xiong, Bing,et al. Salvicine functions as novel topoisomerase II poison by binding to ATP pocket[J]. MOLECULAR PHARMACOLOGY,2006,70(5):1593-1601.
APA	Hu, Chao-Xin.,Zuo, Zhi-Li.,Xiong, Bing.,Ma, Jin-Gui.,Geng, Mei-Yu.,...&Ding, Jian.(2006).Salvicine functions as novel topoisomerase II poison by binding to ATP pocket.MOLECULAR PHARMACOLOGY,70(5),1593-1601.
MLA	Hu, Chao-Xin,et al."Salvicine functions as novel topoisomerase II poison by binding to ATP pocket".MOLECULAR PHARMACOLOGY 70.5(2006):1593-1601.