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

Research output: Contribution to journalArticle

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

Abstract

The arabinosyltransferases EmbA, EmbB, and EmbC are involved in Mycobacterium tuberculosis cell wall synthesis and are recognized as the targets for the anti-tuberculosis drug ethambutol. We have 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 by binding to the same site as both substrates in EmbB and EmbC. The majority of drug-resistant mutations are located nearby to the ethambutol-binding site. Collectively, our work provides a structural basis for understanding the biochemical function and inhibition of arabinosyltransferases and development of new anti-tuberculosis agents.

Bibliographic note

Copyright © 2020, American Association for the Advancement of Science.

Details

Original languageEnglish
JournalScience
Publication statusE-pub ahead of print - 23 Apr 2020