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Structures of cell wall arabinosyltransferases with the anti-tuberculosis drug ethambutol

DOI: 10.1126/science.aba9102 DOI Help

Authors: Lu Zhang (ShanghaiTech University; Nankai University) , Yao Zhao (ShanghaiTech University; Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences; University of Chinese Academy of Sciences) , Yan Gao (Tsinghua University) , Lijie Wu (ShanghaiTech University) , Ruogu Gao (University of Chinese Academy of Science; Institute of Biophysics, Chinese Academy of Sciences) , Qi Zhang (ShanghaiTech University) , Yinan Wang (ShanghaiTech University; University of Chinese Academy of Sciences) , Chengyao Wu (ShanghaiTech University) , Fangyu Wu (Nankai University) , Sudagar S. Gurcha (University of Birmingham) , Natacha Veerapen (University of Birmingham) , Sarah M. Batt (University of Birmingham) , Wei Zhao (Nankai University) , Ling Qin (ShanghaiTech University) , Xiuna Yang (ShanghaiTech University) , Manfu Wang (ShanghaiTech University) , Yan Zhu (ShanghaiTech University) , Bing Zhang (ShanghaiTech University) , Lijun Bi (Institute of Biophysics, Chinese Academy of Sciences) , Xian’en Zhang (Institute of Biophysics, Chinese Academy of Sciences) , Haitao Yang (ShanghaiTech University) , Luke W. Guddat (The University of Queensland) , Wenqing Xu (ShanghaiTech University) , Quan Wang (ShanghaiTech University; Institute of Biophysics, Chinese Academy of Sciences) , Jun Li (ShanghaiTech University) , Gurdyal S. Besra (University of Birmingham) , Zihe Rao (ShanghaiTech University; Nankai University; Tsinghua University; Institute of Biophysics, Chinese Academy of Sciences)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Science , VOL 4

State: Published (Approved)
Published: April 2020

Abstract: The arabinosyltransferases EmbA, EmbB, and EmbC are involved in Mycobacterium tuberculosis cell wall synthesis and are recognized as the targets for the anti-tuberculosis drug ethambutol. We have determined cryo-electron microscopy and x-ray crystal structures of mycobacterial EmbA-EmbB and EmbC-EmbC complexes, in the presence of their glycosyl donor and acceptor substrates and with ethambutol. These structures show how the donor and acceptor substrates bind in the active site and how ethambutol inhibits by binding to the same site as both substrates in EmbB and EmbC. The majority of drug-resistant mutations are located nearby to the ethambutol-binding site. Collectively, our work provides a structural basis for understanding the biochemical function and inhibition of arabinosyltransferases and development of new anti-tuberculosis agents.

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)

Other Facilities: Shanghai Synchrotron Radiation Facility; SPring-8; Swiss Light Source