Author:
Zhang Lu,Zhao Yao,Gao Ruogu,Li Jun,Yang Xiuna,Gao Yan,Zhao Wei,Gurcha Sudagar S.,Veerapen Natacha,Batt Sarah M.,Besra Kajelle Kaur,Xu Wenqing,Bi Lijun,Zhang Xian’en,Guddat Luke W.,Yang Haitao,Wang Quan,Besra Gurdyal S.,Rao Zihe
Abstract
AbstractInhibition 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.
Publisher
Springer Science and Business Media LLC
Subject
Cell Biology,Drug Discovery,Biochemistry,Biotechnology
Cited by
17 articles.
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