Journal
PROTEIN & CELL
Volume 11, Issue 7, Pages 505-517Publisher
SPRINGER
DOI: 10.1007/s13238-020-00726-6
Keywords
Mycobacterium tuberculosis; EmbB; cryo-EM; ethambutol; cell wall synthesis; arabinoglacatan; arabinosyltransferase; acyl-carrier-protein; drug discovery
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Funding
- National Key RAMP
- D Program of China [2017YFC0840300]
- Project of International Cooperation and Exchanges NSFC [81520108019]
- Chinese Academy of Sciences [XDB29020000]
- Medical Research Council [MR/S000542/1]
- MRC [MR/S000542/1] Funding Source: UKRI
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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.
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