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

Science (New York, N.Y.) 2020 Jun 12

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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. Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Citation

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. Structures of cell wall arabinosyltransferases with the anti-tuberculosis drug ethambutol. Science (New York, N.Y.). 2020 Jun 12;368(6496):1211-1219