Crystal structure of Drosophila melanogaster tryptophan 2,3-dioxygenase reveals insights into substrate recognition and catalytic mechanism

	Crystal structure of Drosophila melanogaster tryptophan 2,3-dioxygenase reveals insights into substrate recognition and catalytic mechanism
	Huang, W; Gong, Z; Li, J; Ding, JP
刊名	JOURNAL OF STRUCTURAL BIOLOGY
	2013
卷号	181 期号:3 页码:291-299
关键词	Tryptophan 2 Kynurenine pathway Catalytic mechanism Crystal structure 3-dioxygenase
通讯作者	Ding, JP (reprint author), Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, State Key Lab Mol Biol, 320 Yue Yang Rd, Shanghai 200031, Peoples R China.,jpding@sibcb.ac.cn
英文摘要	Tryptophan 2,3-dioxygenase (TDO) catalyzes the oxidative cleavage of the indole ring of L-tryptophan to N-formylkynurenine in the kynurenine pathway, and is considered as a drug target for cancer immunotherapy. Here, we report the first crystal structure of a eukaryotic TDO from Drosophila melanogaster (DmTDO) in complex with heme at 2.7 angstrom resolution. DmTDO consists of an N-terminal segment, a large domain and a small domain, and assumes a tetrameric architecture. Compared with prokaryotic TDOs, DmTDO contains two major insertion sequences: one forms part of the heme-binding site and the other forms a large portion of the small domain. The small domain which is unique to eukaryotic TDOs, interacts with the active site of an adjacent monomer and plays a role in the catalysis. Molecular modeling and dynamics simulation of DmTDO-heme-Trp suggest that like prokaryotic TDOs, DmTDO adopts an induced-fit mechanism to bind L-Trp; in particular, two conserved but flexible loops undergo conformational changes, converting the active site from an open conformation to a closed conformation. The functional roles of the key residues involved in recognition and binding of the heme and the substrate are verified by mutagenesis and kinetic studies. In addition, a modeling study of DmTDO in complex with the competitive inhibitor LM10 provides useful information for further inhibitor design. These findings reveal insights into the substrate recognition and the catalysis of DmTDO and possibly other eukaryotic TDOs and shed lights on the development of effective anti-TDO inhibitors. (c) 2013 Elsevier Inc. All rights reserved.
学科主题	Biochemistry & Molecular Biology; Biophysics; Cell Biology
类目[WOS]	Biochemistry & Molecular Biology ; Biophysics ; Cell Biology
关键词[WOS]	INDOLEAMINE 2,3-DIOXYGENASE ; DIOXYGENASE ; TOLERANCE ; EXPRESSION ; INHIBITION ; CATABOLISM ; CANCER
收录类别	SCI
语种	英语
WOS记录号	WOS:000315549600010
内容类型	期刊论文
版本	出版稿
源URL	[http://202.127.25.143/handle/331003/362]
专题	上海生化细胞研究所_上海生科院生化细胞研究所
推荐引用方式 GB/T 7714	Huang, W,Gong, Z,Li, J,et al. Crystal structure of Drosophila melanogaster tryptophan 2,3-dioxygenase reveals insights into substrate recognition and catalytic mechanism[J]. JOURNAL OF STRUCTURAL BIOLOGY,2013,181(3):291-299.
APA	Huang, W,Gong, Z,Li, J,&Ding, JP.(2013).Crystal structure of Drosophila melanogaster tryptophan 2,3-dioxygenase reveals insights into substrate recognition and catalytic mechanism.JOURNAL OF STRUCTURAL BIOLOGY,181(3),291-299.
MLA	Huang, W,et al."Crystal structure of Drosophila melanogaster tryptophan 2,3-dioxygenase reveals insights into substrate recognition and catalytic mechanism".JOURNAL OF STRUCTURAL BIOLOGY 181.3(2013):291-299.