Structures of cell wall arabinosyltransferases with the anti-tuberculosis drug ethambutol

被引：112

作者：

Zhang, Lu ^{[1
,2
]}

Zhao, Yao ^{[1
,3
,4
]}

Gao, Yan ^{[5
]}

Wu, Lijie ^{[1
]}

Gao, Ruogu ^{[4
,6
,7
]}

Zhang, Qi ^{[1
]}

Wang, Yinan ^{[1
,4
]}

Wu, Chengyao ^{[1
]}

Wu, Fangyu ^{[2
]}

Gurcha, Sudagar S. ^{[8
]}

Veerapen, Natacha ^{[8
]}

Batt, Sarah M. ^{[8
]}

Zhao, Wei ^{[2
]}

Qin, Ling ^{[1
,10
]}

Yang, Xiuna ^{[1
]}

Wang, Manfu ^{[1
]}

Zhu, Yan ^{[1
]}

Zhang, Bing ^{[1
]}

Bi, Lijun ^{[6
,7
]}

Zhang, Xian'en ^{[6
,7
]}

Yang, Haitao ^{[1
]}

Guddat, Luke W. ^{[9
]}

Xu, Wenqing ^{[1
]}

Wang, Quan ^{[1
,6
,7
]}

Li, Jun ^{[1
]}

Besra, Gurdyal S. ^{[8
]}

Rao, Zihe ^{[1
,2
,5
,6
,7
]}

机构：

[1] ShanghaiTech Univ, Shanghai Inst Adv Immunochem Studies, iHuman Inst, Sch Life Sci & Technol, Shanghai 201210, Peoples R China

[2] Nankai Univ, Coll Life Sci, Coll Pharm, Frontiers Sci Ctr Cell Response,State Key Lab Med, Tianjin 300353, Peoples R China

[3] Chinese Acad Sci, Shanghai Inst Biochem & Cell Biol, CAS Ctr Excellence Mol Cell Sci, Shanghai 200031, Peoples R China

[4] Univ Chinese Acad Sci, Beijing 100101, Peoples R China

[5] Tsinghua Univ, Lab Struct Biol, Beijing 100084, Peoples R China

[6] Chinese Acad Sci, Inst Biophys, CAS Ctr Excellence Biomacromol, Natl Lab Biomacromol, Beijing 100101, Peoples R China

[7] Chinese Acad Sci, Inst Biophys, CAS Ctr Excellence Biomacromol, Key Lab RNA Biol, Beijing 100101, Peoples R China

[8] Univ Birmingham, Inst Microbiol & Infect, Sch Biosci, Birmingham B15 2TT, W Midlands, England

[9] Univ Queensland, Sch Chem & Mol Biosci, Brisbane, Qld 4072, Australia

[10] Univ Oxford, Div Struct Biol, Oxford OX3 7BN, England

来源：

SCIENCE | 2020年 / 368卷 / 6496期

基金：

国家重点研发计划; 英国医学研究理事会;

关键词：

ACYL CARRIER PROTEIN; MYCOBACTERIUM-TUBERCULOSIS; CRYSTAL-STRUCTURES; ARABINAN BIOSYNTHESIS; EMBB GENE; RESISTANCE; MUTATION; GLYCOSYLTRANSFERASES; LIPOARABINOMANNAN; ARABINOGALACTAN;

D O I：

10.1126/science.aba9102

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：1211 / +

页数：65

共 63 条

[11] Mycobacterial lipoarabinomannan and related lipoglycans: from biogenesis to modulation of the immune response [J].