1. Academic Validation
  2. Structural Basis for the Inhibition of Mycobacterial MmpL3 by NITD-349 and SPIRO

Structural Basis for the Inhibition of Mycobacterial MmpL3 by NITD-349 and SPIRO

  • J Mol Biol. 2020 Jul 24;432(16):4426-4434. doi: 10.1016/j.jmb.2020.05.019.
Xiaolin Yang 1 Tianyu Hu 2 Xiuna Yang 2 Wenqing Xu 2 Haitao Yang 2 Luke W Guddat 3 Bing Zhang 4 Zihe Rao 5
Affiliations

Affiliations

  • 1 Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100101, China.
  • 2 Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
  • 3 School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD, 4072, Australia.
  • 4 Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China. Electronic address: zhangbing@shanghaitech.edu.cn.
  • 5 Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300353, China; National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; Laboratory of Structural Biology, Tsinghua University, Beijing 100084, China.
Abstract

Novel antitubercular agents are urgently needed to combat the emergence of global drug resistance to human tuberculosis. Mycobacterial membrane protein Large 3 (MmpL3) is a promising drug target because its activity is essential and required for cell-wall biosynthesis. Several classes of MmpL3 inhibitors have been developed against Mycobacterium tuberculosis (Mtb) with potent anti-tuberculosis activity. These include the drug candidate SQ109, which has progressed to phase IIb/III clinical trials. Here, we have determined the crystal structures of MmpL3 in complex with NITD-349 and SPIRO. Both inhibitors bind deep in the central channel of transmembrane domain and cause conformational changes to the protein. The amide nitrogen and indole nitrogen of NITD-349 and the piperidine nitrogen of SPIRO interact and clamp Asp645. Structural analysis of the two structures reveals that these inhibitors target the proton relay pathway to block the activity of MmpL3. The findings presented here enrich our understanding of the binding modes of MmpL3 inhibitors and provide directions to enable further rational drug design targeting MmpL3.

Keywords

MmpL3; Mycobacterium tuberculosis; NITD-349; SPIRO; mycobacterial membrane protein Large.

Figures
Products