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Crystal Structures of Membrane Transporter MmpL3, an Anti-TB Drug Target

文献类型：期刊论文

作者Zhang, Bing1,2,3,10; Li, Jun1,2,3; Yang, Xiaolin1,2,3,10; Wu, Lijie7; Zhang, Jia1,2; Yang, Yang1,2,5; Zhao, Yao1,2,3,10; Zhang, Lu1,2,4; Yang, Xiuna1,2; Yang, Xiaobao1,2
刊名CELL
出版日期2019-01-24
卷号176期号:3页码:636-+
ISSN号0092-8674
DOI10.1016/j.cell.2019.01.003
通讯作者Li, Jun(lijun1@shanghaitech.edu.cn) ; Yang, Haitao(yanght@shanghaitech.edu.cn) ; Rao, Zihe(raozh@mail.tsinghua.edu.cn)
英文摘要Despite intensive efforts to discover highly effective treatments to eradicate tuberculosis (TB), it remains as a major threat to global human health. For this reason, new TB drugs directed toward new targets are highly coveted. MmpLs (Mycobacterial membrane proteins Large), which play crucial roles in transporting lipids, polymers and immunomodulators and which also extrude therapeutic drugs, are among the most important therapeutic drug targets to emerge in recent times. Here, crystal structures of mycobacterial MmpL3 alone and in complex with four TB drug candidates, including SQ109 (in Phase 2b-3 clinical trials), are reported. MmpL3 consists of a periplasmic pore domain and a twelve-helix transmembrane domain. Two Asp-Tyr pairs centrally located in this domain appear to be key facilitators of proton-translocation. SQ109, AU1235, ICA38, and rimonabant bind inside the transmembrane region and disrupt these Asp-Tyr pairs. This structural data will greatly advance the development of MmpL3 inhibitors as new TB drugs.
WOS关键词MYCOLIC ACID TRANSPORT ; CATALASE-PEROXIDASE GENE ; MYCOBACTERIUM-TUBERCULOSIS ; ISONIAZID RESISTANCE ; ANTITUBERCULAR DRUG ; SQ109 ; INHIBITORS ; DISCOVERY ; INSIGHTS ; FAMILY
资助项目National Key Research and Development Program of China[2017YFC0840300] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDB08020200] ; State Key Development Program for Basic Research of the Ministry of Science and Technology of China (973 Project)[2014CB542800] ; State Key Development Program for Basic Research of the Ministry of Science and Technology of China (973 Project)[2014CBA02003] ; National Natural Science Foundation of China[813300237] ; National Natural Science Foundation of China[31500607] ; National Natural Science Foundation of China[81520108019]
WOS研究方向Biochemistry & Molecular Biology ; Cell Biology
语种英语
WOS记录号WOS:000456526100021
出版者CELL PRESS
源URL[http://119.78.100.183/handle/2S10ELR8/290783]  
专题中国科学院上海药物研究所
通讯作者Li, Jun; Yang, Haitao; Rao, Zihe
作者单位1.ShanghaiTech Univ, Shanghai Inst Adv Immunochem Studies, Shanghai 201210, Peoples R China
2.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Biochem & Cell Biol, CAS Ctr Excellence Mol Cell Sci, Shanghai 200031, Peoples R China
4.Nankai Univ, State Key Lab Med Chem Biol, Tianjin 300353, Peoples R China
5.Chinese Acad Sci, Inst Biophys, CAS Ctr Excellence Biomacromol, Natl Lab Biomacromol, Beijing 100101, Peoples R China
6.Tsinghua Univ, Struct Biol Lab, Beijing 100084, Peoples R China
7.ShanghaiTech Univ, iHuman Inst, Shanghai 201210, Peoples R China
8.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, Shanghai 201203, Peoples R China
9.Univ Queensland, Sch Chem & Mol Biosci, Brisbane, Qld 4072, Australia
10.Univ Chinese Acad Sci, Beijing 100101, Peoples R China
推荐引用方式
GB/T 7714		 Zhang, Bing,Li, Jun,Yang, Xiaolin,et al. Crystal Structures of Membrane Transporter MmpL3, an Anti-TB Drug Target[J]. CELL,2019,176(3):636-+.
APA Zhang, Bing.,Li, Jun.,Yang, Xiaolin.,Wu, Lijie.,Zhang, Jia.,...&Rao, Zihe.(2019).Crystal Structures of Membrane Transporter MmpL3, an Anti-TB Drug Target.CELL,176(3),636-+.
MLA Zhang, Bing,et al."Crystal Structures of Membrane Transporter MmpL3, an Anti-TB Drug Target".CELL 176.3(2019):636-+.

入库方式： OAI收割

来源：上海药物研究所

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