The cell wall is a key drug target in Mycobacterium tuberculosis. The arabinosyltransferases EmbA, EmbB and EmbC are involved in the synthesis of the complex mycobacterial cell wall, and they are regarded as a target of the anti-tuberculosis drug ethambutol, as mutations in these proteins result in clinically resistant strains. The enzyme structures, their mechanism of action as well as the mode of action of ethambutol remained unknown. Zhang et al. determined the cryo–electron microscopy structures of heterodimeric EmbA–EmbB and homodimeric EmbC complexes, showing how the donor and acceptor substrates bind in the active site, providing insights into how arabinose is transferred. Ethambutol binds to the same site as the substrates in the EmbB and EmbC subunits, which suggests that the drug inhibits the enzymes by competing for binding. Finally, ethambutol-resistance mutations are located close to the ethambutol-binding site.
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Zhang, L. et al. Structures of cell wall arabinosyltransferases with the anti-tuberculosis drug ethambutol. Science 368, 1211–1219 (2020)
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Du Toit, A. Catching the mode of action. Nat Rev Microbiol 18, 476 (2020). https://doi.org/10.1038/s41579-020-0411-2
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DOI: https://doi.org/10.1038/s41579-020-0411-2