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.
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.
Cell. 2019 Jan 24;176(3):636-648.e13. doi: 10.1016/j.cell.2019.01.003.
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.
尽管人们努力寻找高效的治疗方法来根除结核病 (TB)，但它仍然是全球人类健康的主要威胁。出于这个原因，针对新靶点的新型结核病药物备受追捧。MmpLs（分枝杆菌膜蛋白大型）在运输脂质、聚合物和免疫调节剂以及排出治疗药物方面发挥着至关重要的作用，是近年来出现的最重要的治疗药物靶点之一。在这里，报道了单独的分枝杆菌 MmpL3 及其与四种结核病药物候选物（包括处于 2b-3 期临床试验阶段的 SQ109）的复合物的晶体结构。MmpL3 由周质孔域和十二螺旋跨膜域组成。该域中央的两对 Asp-Tyr 似乎是质子转运的关键促进剂。SQ109、AU1235、ICA38 和利莫那班结合在跨膜区域内并破坏这些 Asp-Tyr 对。这些结构数据将极大地促进 MmpL3 抑制剂作为新型结核病药物的开发。
