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

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 center dot EF-Ts and EF-Tu center dot 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. Crystal structures of M. tuberculosis elongation factors EF-Tu and EF-Ts in complex and GDP-bound Ef-Tu reveal the molecular basis of EF-Tu's representative recycling and inactive forms in protein translation.

Automated summary

Crystal structures of M. tuberculosis elongation factors EF-Tu and EF-Ts in complex and GDP-bound Ef-Tu reveal the molecular basis of EF-Tu's representative recycling and inactive forms in protein translation. The FDA-approved drug Osimertinib inhibits the growth of related strains by directly binding with EF-Tu.