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

Lu Zhang; Yao Zhao; Yan Gao; Lijie Wu; Ruogu Gao; Qi Zhang; Yinan Wang; Chengyao Wu; Fangyu Wu; Sudagar S Gurcha; Natacha Veerapen; Sarah M Batt; Wei Zhao; Ling Qin; Xiuna Yang; Manfu Wang; Yan Zhu; Bing Zhang; Lijun Bi; Xian'en Zhang; Haitao Yang; Luke W Guddat; Wenqing Xu; Quan Wang; Jun Li; Gurdyal S Besra; Zihe Rao

doi:10.1126/science.aba9102

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

Lu Zhang, Yao Zhao, Yan Gao, Lijie Wu, Ruogu Gao, Qi Zhang, Yinan Wang, Chengyao Wu, Fangyu Wu, Sudagar S Gurcha, Natacha Veerapen, Sarah M Batt, Wei Zhao, Ling Qin, Xiuna Yang, Manfu Wang, Yan Zhu, Bing Zhang, Lijun Bi, Xian'en ZhangHaitao Yang, Luke W Guddat, Wenqing Xu, Quan Wang, Jun Li, Gurdyal S Besra, Zihe Rao

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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.

Original language	English
Pages (from-to)	1211-1219
Number of pages	9
Journal	Science
Volume	368
Issue number	6496
Early online date	23 Apr 2020
DOIs	https://doi.org/10.1126/science.aba9102
Publication status	Published - 12 Jun 2020

Bibliographical note

Keywords

Antitubercular Agents/chemistry
Cell Wall/enzymology
Cryoelectron Microscopy
Drug Resistance, Multiple, Bacterial
Ethambutol/chemistry
Mycobacterium tuberculosis/enzymology
Pentosyltransferases/chemistry
Protein Conformation

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Science Final PDF 2020
This is the author’s version of the work. It is posted here by permission of the AAAS for personal use, not for redistribution. The definitive version was published in Science 368, DOI: 10.1126/science.aba9102
Accepted author manuscript, 47.6 MBLicence: None: All rights reserved

https://doi.org/10.1126/science.aba9102Licence: None: All rights reserved

Cite this

Zhang, L., Zhao, Y., Gao, Y., Wu, L., Gao, R., Zhang, Q., Wang, Y., Wu, C., Wu, F., Gurcha, S. S., Veerapen, N., Batt, S. M., Zhao, W., Qin, L., Yang, X., Wang, M., Zhu, Y., Zhang, B., Bi, L., ... Rao, Z. (2020). Structures of cell wall arabinosyltransferases with the anti-tuberculosis drug ethambutol. Science, 368(6496), 1211-1219. Advance online publication. https://doi.org/10.1126/science.aba9102

@article{1bb50aded3b14ca3bd9ab82e753aaf00,

title = "Structures of cell wall arabinosyltransferases with the anti-tuberculosis drug ethambutol",

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.",

keywords = "Antitubercular Agents/chemistry, Cell Wall/enzymology, Cryoelectron Microscopy, Drug Resistance, Multiple, Bacterial, Ethambutol/chemistry, Mycobacterium tuberculosis/enzymology, Pentosyltransferases/chemistry, Protein Conformation",

author = "Lu Zhang and Yao Zhao and Yan Gao and Lijie Wu and Ruogu Gao and Qi Zhang and Yinan Wang and Chengyao Wu and Fangyu Wu and Gurcha, {Sudagar S} and Natacha Veerapen and Batt, {Sarah M} and Wei Zhao and Ling Qin and Xiuna Yang and Manfu Wang and Yan Zhu and Bing Zhang and Lijun Bi and Xian'en Zhang and Haitao Yang and Guddat, {Luke W} and Wenqing Xu and Quan Wang and Jun Li and Besra, {Gurdyal S} and Zihe Rao",

note = "Copyright {\textcopyright} 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.",

year = "2020",

month = jun,

day = "12",

doi = "10.1126/science.aba9102",

language = "English",

volume = "368",

pages = "1211--1219",

journal = "Science",

issn = "0036-8075",

publisher = "American Association for the Advancement of Science",

number = "6496",

}

Zhang, L, Zhao, Y, Gao, Y, Wu, L, Gao, R, Zhang, Q, Wang, Y, Wu, C, Wu, F, Gurcha, SS, Veerapen, N, Batt, SM, Zhao, W, Qin, L, Yang, X, Wang, M, Zhu, Y, Zhang, B, Bi, L, Zhang, X, Yang, H, Guddat, LW, Xu, W, Wang, Q, Li, J, Besra, GS & Rao, Z 2020, 'Structures of cell wall arabinosyltransferases with the anti-tuberculosis drug ethambutol', Science, vol. 368, no. 6496, pp. 1211-1219. https://doi.org/10.1126/science.aba9102

TY - JOUR

T1 - Structures of cell wall arabinosyltransferases with the anti-tuberculosis drug ethambutol

AU - Zhang, Lu

AU - Zhao, Yao

AU - Gao, Yan

AU - Wu, Lijie

AU - Gao, Ruogu

AU - Zhang, Qi

AU - Wang, Yinan

AU - Wu, Chengyao

AU - Wu, Fangyu

AU - Gurcha, Sudagar S

AU - Veerapen, Natacha

AU - Batt, Sarah M

AU - Zhao, Wei

AU - Qin, Ling

AU - Yang, Xiuna

AU - Wang, Manfu

AU - Zhu, Yan

AU - Zhang, Bing

AU - Bi, Lijun

AU - Zhang, Xian'en

AU - Yang, Haitao

AU - Guddat, Luke W

AU - Xu, Wenqing

AU - Wang, Quan

AU - Li, Jun

AU - Besra, Gurdyal S

AU - Rao, Zihe

PY - 2020/6/12

Y1 - 2020/6/12

N2 - 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.

AB - 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.

KW - Antitubercular Agents/chemistry

KW - Cell Wall/enzymology

KW - Cryoelectron Microscopy

KW - Drug Resistance, Multiple, Bacterial

KW - Ethambutol/chemistry

KW - Mycobacterium tuberculosis/enzymology

KW - Pentosyltransferases/chemistry

KW - Protein Conformation

UR - http://www.scopus.com/inward/record.url?scp=85084217743&partnerID=8YFLogxK

U2 - 10.1126/science.aba9102

DO - 10.1126/science.aba9102

M3 - Article

C2 - 32327601

SN - 0036-8075

VL - 368

SP - 1211

EP - 1219

JO - Science

JF - Science

IS - 6496

ER -

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

Abstract

Bibliographical note

Keywords

UN SDGs

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