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

Research output: Contribution to journalArticlepeer-review

Authors

  • Lu Zhang
  • Yao Zhao
  • Yan Gao
  • Lijie Wu
  • Ruogu Gao
  • Qi Zhang
  • Yinan Wang
  • Chengyao Wu
  • Fangyu Wu
  • 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
  • Zihe Rao

Colleges, School and Institutes

External organisations

  • Nankai University
  • Chinese Academy of Sciences
  • Tsinghua University
  • ShanghaiTech University
  • Max Planck Institute for Biophysics
  • University of Queensland

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.

Bibliographic note

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

Details

Original languageEnglish
Pages (from-to)1211-1219
Number of pages9
JournalScience
Volume368
Issue number6496
Early online date23 Apr 2020
Publication statusPublished - 12 Jun 2020

Keywords

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

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