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Crystal structures of membrane transporter MmpL3, an anti-TB drug target

DOI: 10.1016/j.cell.2019.01.003 DOI Help

Authors: Bing Zhang (ShanghaiTech University; Shanghai Institute of Biochemistry and Cell Biology; University of Chinese Academy of Sciences) , Jun Li (ShanghaiTech University; Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences) , Xiaolin Yang (ShanghaiTech University; Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences) , Lijie Wu (ShanghaiTech University) , Jia Zhang (ShanghaiTech University) , Yang Yang (ShanghaiTech University; CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences) , Yao Zhao (ShanghaiTech University; CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences) , Lu Zhang (ShanghaiTech University; Nankai University) , Xiuna Yang (ShanghaiTech University) , Xiaobao Yang (ShanghaiTech University) , Xi Cheng (Institute of Materia Medica, Chinese Academy of Sciences) , Zhijie Liu (ShanghaiTech University) , Biao Jiang (ShanghaiTech University) , Hualiang Jiang (Shanghai Institute of Materia Medica, Chinese Academy of Sciences) , Luke W. Guddat (The University of Queensland) , Haitao Yang (ShanghaiTech University) , Zihe Rao (ShanghaiTech University; Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences; Nankai University; Institute of Biophysics, Chinese Academy of Sciences)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Cell , VOL 176 , PAGES 636 - 648.e13

State: Published (Approved)
Published: January 2019

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.

Diamond Keywords: Tuberculosis (TB); Bacteria

Subject Areas: Biology and Bio-materials, Medicine


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

Other Facilities: Shanghai Synchrotron Radiation Facility (SSRF); Spring 8

Added On: 30/01/2019 09:04

Discipline Tags:

Pathogens Infectious Diseases Health & Wellbeing Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)