2. Academic Validation
  3. Crystal Structures of Membrane Transporter MmpL3, an Anti-TB Drug Target

Crystal Structures of Membrane Transporter MmpL3, an Anti-TB Drug Target

  • Cell. 2019 Jan 24;176(3):636-648.e13. doi: 10.1016/j.cell.2019.01.003.
Bing Zhang 1,  Jun Li 2,  Xiaolin Yang 1,  Lijie Wu 3,  Jia Zhang 4,  Yang Yang 5,  Yao Zhao 1,  Lu Zhang 6,  Xiuna Yang 4,  Xiaobao Yang 4,  Xi Cheng 7,  Zhijie Liu 3,  Biao Jiang 4,  Hualiang Jiang 7,  Luke W Guddat 8,  Haitao Yang 9,  Zihe Rao 10
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; CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, 200031, China. Electronic address: lijun1@shanghaitech.edu.cn.
  • 3 iHuman Institute, ShanghaiTech University, Shanghai, 201210, China.
  • 4 Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
  • 5 Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China; National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
  • 6 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.
  • 7 Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 8 School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, Australia.
  • 9 Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China. Electronic address: yanght@shanghaitech.edu.cn.
  • 10 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; 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. Electronic address: raozh@mail.tsinghua.edu.cn.
PMID: 30682372 DOI: 10.1016/j.cell.2019.01.003
Abstract

Despite intensive efforts to discover highly effective treatments to eradicate tuberculosis (TB), it remains as a major threat to global human health. For this reason, new TB drugs directed toward new targets are highly coveted. MmpLs (Mycobacterial membrane proteins Large), which play crucial roles in transporting lipids, Polymers and immunomodulators and which also extrude therapeutic drugs, are among the most important therapeutic drug targets to emerge in recent times. Here, crystal structures of mycobacterial MmpL3 alone and in complex with four TB drug candidates, including SQ109 (in Phase 2b-3 clinical trials), are reported. MmpL3 consists of a periplasmic pore domain and a twelve-helix transmembrane domain. Two Asp-Tyr pairs centrally located in this domain appear to be key facilitators of proton-translocation. SQ109, AU1235, ICA38, and rimonabant bind inside the transmembrane region and disrupt these Asp-Tyr pairs. This structural data will greatly advance the development of MmpL3 inhibitors as new TB drugs.

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