Cryo-EM snapshots of mycobacterial arabinosyltransferase complex EmbB-AcpM.
10.1007/s13238-020-00726-6
- Author:
Lu ZHANG
1
;
Yao ZHAO
2
;
Ruogu GAO
3
;
Jun LI
2
;
Xiuna YANG
2
;
Yan GAO
4
;
Wei ZHAO
1
;
Sudagar S GURCHA
5
;
Natacha VEERAPEN
5
;
Sarah M BATT
5
;
Kajelle Kaur BESRA
5
;
Wenqing XU
2
;
Lijun BI
6
;
Xian'en ZHANG
6
;
Luke W GUDDAT
7
;
Haitao YANG
2
;
Quan WANG
8
;
Gurdyal S BESRA
9
;
Zihe RAO
10
Author Information
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. University of Chinese Academy of Sciences, Beijing, 100101, China.
4. Laboratory of Structural Biology, Tsinghua University, Beijing, 100084, China.
5. School of Biosciences, Institute of Microbiology and Infection, University of Birmingham, Birmingham, B15 2TT, UK.
6. National Laboratory of Biomacromolecules and Key Laboratory of RNA Biology, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, CAS, Beijing, 100101, China.
7. School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD, 4072, Australia.
8. Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China. wangq@ibp.ac.cn.
9. School of Biosciences, Institute of Microbiology and Infection, University of Birmingham, Birmingham, B15 2TT, UK. G.Besra@bham.ac.uk.
10. State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and College of Pharmacy, Nankai University, Tianjin, 300353, China. raozh@tsinghua.edu.cn.
- Publication Type:Journal Article
- Keywords:
EmbB;
Mycobacterium tuberculosis;
acyl-carrier-protein;
arabinoglacatan;
arabinosyltransferase;
cell wall synthesis;
cryo-EM;
drug discovery;
ethambutol
- From:
Protein & Cell
2020;11(7):505-517
- CountryChina
- Language:English
-
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.
