Protein & Cell >

2020 , Vol. 11 >Issue 7: 505 - 517

DOI: https://doi.org/10.1007/s13238-020-00726-6

RESEARCH ARTICLE

Cryo-EM snapshots of mycobacterial arabinosyltransferase complex EmbB2-AcpM2

  • Lu Zhang 1 ,
  • Yao Zhao 2,3,4 ,
  • Ruogu Gao 4,5 ,
  • Jun Li 2 ,
  • Xiuna Yang 2 ,
  • Yan Gao 6 ,
  • Wei Zhao 1 ,
  • Sudagar S. Gurcha 7 ,
  • Natacha Veerapen 7 ,
  • Sarah M. Batt 7 ,
  • Kajelle Kaur Besra 7 ,
  • Wenqing Xu 2 ,
  • Lijun Bi 5 ,
  • Xian’en Zhang 5 ,
  • Luke W. Guddat8 8 ,
  • Haitao Yang 2 ,
  • Quan Wang , 2,5 ,
  • Gurdyal S. Besra , 7 ,
  • Zihe Rao , 1,2,5,6
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  • 1. State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and College of Pharmacy, Nankai University, Tianjin 300353, China
  • 2. Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
  • 3. CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences (CAS), Shanghai 200031, China
  • 4. University of Chinese Academy of Sciences, Beijing 100101, China
  • 5. National Laboratory of Biomacromolecules and Key Laboratory of RNA Biology, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, CAS, Beijing 100101, China
  • 6. 6Laboratory of Structural Biology, Tsinghua University, Beijing 100084, China
  • 7. School of Biosciences, Institute of Microbiology and Infection, University of Birmingham, Birmingham B15 2TT, UK
  • 8. School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, Australia

Received date: 12 Nov 2019

Accepted date: 27 Nov 2019

Published date: 15 Jul 2020

Copyright

2020 The Author(s) 2020
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Abstract

Inhibition of Mycobacterium tuberculosis (Mtb) cell wall assembly is an established strategy for anti-TB chemotherapy. Arabinosyltransferase EmbB, which catalyzes the transfer of arabinose from the donor decaprenyl-phosphate-arabinose (DPA) to its arabinosyl acceptor is an essential enzyme for Mtb cell wall synthesis. Analysis of drug resistance mutations suggests that EmbB is the main target of the front-line anti-TB drug, ethambutol. Herein, we report the cryo-EM structures of Mycobacterium smegmatis EmbB in its “resting state” and DPA-bound “active state”. EmbB is a fifteentransmembrane-spanning protein, assembled as a dimer. Each protomer has an associated acyl-carrierprotein (AcpM) on their cytoplasmic surface. Conformational changes upon DPA binding indicate an asymmetric movement within the EmbB dimer during catalysis. Functional studies have identified critical residues in substrate recognition and catalysis, and demonstrated that ethambutol inhibits transferase activity of EmbB by competing with DPA. The structures represent the first step directed towards a rational approach for anti-TB drug discovery.

Key words： Mycobacterium tuberculosis; EmbB; cryo-EM; ethambutol; cell wall synthesis; arabinoglacatan; arabinosyltransferase; acyl-carrier-protein; drug discovery

Cite this article

Lu Zhang , Yao Zhao , Ruogu Gao , Jun Li , Xiuna Yang , Yan Gao , Wei Zhao , Sudagar S. Gurcha , Natacha Veerapen , Sarah M. Batt , Kajelle Kaur Besra , Wenqing Xu , Lijun Bi , Xian’en Zhang , Luke W. Guddat8 , Haitao Yang , Quan Wang , Gurdyal S. Besra , Zihe Rao . Cryo-EM snapshots of mycobacterial arabinosyltransferase complex EmbB2-AcpM2[J]. Protein & Cell, 2020 , 11(7) : 505 -517 . DOI: 10.1007/s13238-020-00726-6

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