Structures of cell wall arabinosyltransferases with the anti-tuberculosis drug ethambutol
Zhang, Lu1,2,3,4; Zhao, Yao1,2,3,5,6; Gao, Yan7; Wu, Lijie1,2,3; Gao, Ruogu6,8,9; Zhang, Qi1,2,3; Wang, Yinan1,2,3,6; Wu, Chengyao1,2,3; Wu, Fangyu4; Gurcha, Sudagar S.10; Veerapen, Natacha10; Batt, Sarah M.10; Zhao, Wei4; Qin, Ling1,2,3,12; Yang, Xiuna1,2,3; Wang, Manfu1,2,3; Zhu, Yan1,2,3; Zhang, Bing1,2,3; Bi, Lijun8,9; Zhang, Xian'en8,9; Yang, Haitao1,2,3; Guddat, Luke W.11; Xu, Wenqing1,2,3; Wang, Quan1,2,3,8,9; Li, Jun1,2,3; Besra, Gurdyal S.10; Rao, Zihe1,2,3,4,7,8,9
2020-06-12
Source PublicationSCIENCE
ISSN0036-8075
EISSN1095-9203
Volume368Issue:6496Pages:1211
Status已发表
DOI10.1126/science.aba9102
Abstract

The arabinosyltransferases EmbA, EmbB, and EmbC are involved in Mycobacterium tuberculosis cell wall synthesis and are recognized as targets for the anti-tuberculosis drug ethambutol. In this study, we determined cryo-electron microscopy and x-ray crystal structures of mycobacterial EmbA-EmbB and EmbC-EmbC complexes in the presence of their glycosyl donor and acceptor substrates and with ethambutol. These structures show how the donor and acceptor substrates bind in the active site and how ethambutol inhibits arabinosyltransferases by binding to the same site as both substrates in EmbB and EmbC. Most drug-resistant mutations are located near the ethambutol binding site. Collectively, our work provides a structural basis for understanding the biochemical function and inhibition of arabinosyltransferases and the development of new anti-tuberculosis agents.

Indexed BySCI
Funding ProjectNational Key R&D Program of China[2017YFC0840300] ; Project of International Cooperation and Exchanges NSFC[81520108019] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDB29020000] ; Medical Research Council[MR/S000542/1]
WOS Research AreaScience & Technology - Other Topics
WOS SubjectMultidisciplinary Sciences
WOS IDWOS:000544031400026
PublisherAMER ASSOC ADVANCEMENT SCIENCE
WOS KeywordACYL CARRIER PROTEIN ; MYCOBACTERIUM-TUBERCULOSIS ; CRYSTAL-STRUCTURES ; ARABINAN BIOSYNTHESIS ; EMBB GENE ; RESISTANCE ; MUTATION ; GLYCOSYLTRANSFERASES ; LIPOARABINOMANNAN ; ARABINOGALACTAN
Original Document TypeArticle
Citation statistics
Cited Times:22[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Identifierhttps://kms.shanghaitech.edu.cn/handle/2MSLDSTB/121263
Collection免疫化学研究所_PI研究组_张璐组
免疫化学研究所_特聘教授组_饶子和组
iHuman研究所_科学装置(X)_膜蛋白同步辐射线站
生命科学与技术学院_硕士生
生命科学与技术学院_博士生
生命科学与技术学院_PI研究组_许文青组
免疫化学研究所_PI研究组_杨海涛组
免疫化学研究所_PI研究组_王权组
免疫化学研究所_PI研究组_李俊组
Co-First AuthorZhao, Yao
Corresponding AuthorWang, Quan; Li, Jun; Besra, Gurdyal S.; Rao, Zihe
Affiliation1.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.ShanghaiTech Univ, iHuman Inst, Shanghai 201210, Peoples R China
4.Nankai Univ, Coll Life Sci, Coll Pharm, Frontiers Sci Ctr Cell Response,State Key Lab Med, Tianjin 300353, Peoples R China
5.Chinese Acad Sci, Shanghai Inst Biochem & Cell Biol, CAS Ctr Excellence Mol Cell Sci, Shanghai 200031, Peoples R China
6.Univ Chinese Acad Sci, Beijing 100101, Peoples R China
7.Tsinghua Univ, Lab Struct Biol, Beijing 100084, Peoples R China
8.Chinese Acad Sci, Inst Biophys, CAS Ctr Excellence Biomacromol, Natl Lab Biomacromol, Beijing 100101, Peoples R China
9.Chinese Acad Sci, Inst Biophys, CAS Ctr Excellence Biomacromol, Key Lab RNA Biol, Beijing 100101, Peoples R China
10.Univ Birmingham, Inst Microbiol & Infect, Sch Biosci, Birmingham B15 2TT, W Midlands, England
11.Univ Queensland, Sch Chem & Mol Biosci, Brisbane, Qld 4072, Australia
12.Univ Oxford, Div Struct Biol, Oxford OX3 7BN, England
First Author AffilicationShanghai Institute for Advanced Immunochemical Studies;  School of Life Science and Technology;  iHuman Institute
Corresponding Author AffilicationShanghai Institute for Advanced Immunochemical Studies;  School of Life Science and Technology;  iHuman Institute
First Signature AffilicationShanghai Institute for Advanced Immunochemical Studies
Recommended Citation
GB/T 7714
Zhang, Lu,Zhao, Yao,Gao, Yan,et al. Structures of cell wall arabinosyltransferases with the anti-tuberculosis drug ethambutol[J]. SCIENCE,2020,368(6496):1211.
APA Zhang, Lu.,Zhao, Yao.,Gao, Yan.,Wu, Lijie.,Gao, Ruogu.,...&Rao, Zihe.(2020).Structures of cell wall arabinosyltransferases with the anti-tuberculosis drug ethambutol.SCIENCE,368(6496),1211.
MLA Zhang, Lu,et al."Structures of cell wall arabinosyltransferases with the anti-tuberculosis drug ethambutol".SCIENCE 368.6496(2020):1211.
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