Cryo-EM snapshots of mycobacterial arabinosyltransferase complex EmbB2-AcpM2

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 Guddat, Haitao Yang, Quan Wang, Gurdyal S Besra, Zihe Rao

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)
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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 fifteen-transmembrane-spanning protein, assembled as a dimer. Each protomer has an associated acyl-carrier-protein (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.

Original languageEnglish
Pages (from-to)505-517
Number of pages13
JournalProtein & cell
Volume11
Issue number7
Early online date3 May 2020
DOIs
Publication statusPublished - Jul 2020

Keywords

  • EmbB
  • Mycobacterium tuberculosis
  • acyl-carrier-protein
  • arabinoglacatan
  • arabinosyltransferase
  • cell wall synthesis
  • cryo-EM
  • drug discovery
  • ethambutol

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Drug Discovery
  • Cell Biology

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