Structural insights of the elongation factor EF-Tu complexes in protein translation of Mycobacterium tuberculosis

  • Commun Biol. 2022 Oct 3;5(1):1052. doi: 10.1038/s42003-022-04019-y.
Bowen Zhan  1 ,  Yanqing Gao  1 ,  Wenqing Gao  1 ,  Ye Li  1 ,  Zhengyang Li  1 ,  Qi Qi  1 ,  Xin Lan  1 ,  Hongbo Shen  2 ,  Jianhua Gan  1 ,  Guoping Zhao  3 ,  Jixi Li  4  5
Affiliations
  • 1. State Key Laboratory of Genetic Engineering, School of Life Sciences, Shanghai Engineering Research Center of Industrial Microorganisms, Fudan University, 200438, Shanghai, China.
  • 2. Shanghai Clinical Research Center for Infectious Disease (tuberculosis), Shanghai Pulmonary Hospital, Tongji University School of Medicine, 200433, Shanghai, China.
  • 3. Key Laboratory of Synthetic Biology, CAS Center for Excellence in Molecular Plant Sciences, Shanghai Institute of Plant Physiology and Ecology, Chinese Academy of Sciences, 200031, Shanghai, China. [email protected].
  • 4. State Key Laboratory of Genetic Engineering, School of Life Sciences, Shanghai Engineering Research Center of Industrial Microorganisms, Fudan University, 200438, Shanghai, China. [email protected].
  • 5. Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, 200040, Shanghai, China. [email protected].
PMID: 36192483 DOI: 10.1038/s42003-022-04019-y
Abstract

Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) is the second-deadliest infectious disease worldwide. Emerging evidence shows that the elongation factor EF-Tu could be an excellent target for treating Mtb Infection. Here, we report the crystal structures of Mtb EF-Tu•EF-Ts and EF-Tu•GDP complexes, showing the molecular basis of EF-Tu's representative recycling and inactive forms in protein translation. Mtb EF-Tu binds with EF-Ts at a 1:1 ratio in solution and crystal packing. Mutation and SAXS analysis show that EF-Ts residues Arg13, Asn82, and His149 are indispensable for the EF-Tu/EF-Ts complex formation. The GDP binding pocket of EF-Tu dramatically changes conformations upon binding with EF-Ts, sharing a similar GDP-exchange mechanism in E. coli and T. ther. Also, the FDA-approved drug Osimertinib inhibits the growth of M. smegmatis, H37Ra, and M. bovis BCG strains by directly binding with EF-Tu. Thus, our work reveals the structural basis of Mtb EF-Tu in polypeptide synthesis and may provide a promising candidate for TB treatment.

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