Crystal Structures of Membrane Transporter MmpL3, an Anti-TB Drug Target
Crystal Structures of Membrane Transporter MmpL3, an Anti-TB Drug Target
复制标题
抗结核药物靶点膜转运蛋白 MmpL3 的晶体结构
DOI：
10.1016/j.cell.2019.01.003
复制
发表时间：
2019-01-24
期刊：
影响因子：
64.5
通讯作者：
Rao, Zihe
中科院分区：
文献类型：
--
作者：
Zhang, Bing;Li, Jun;Rao, Zihe
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。因此，针对新靶点的新型结核病药物备受追捧。 MmpL（大型分枝杆菌膜蛋白）在转运脂质、聚合物和免疫调节剂方面发挥着至关重要的作用，并且还可以挤出治疗药物，是近年来出现的最重要的治疗药物靶点之一。这里报告了分枝杆菌 MmpL3 单独的晶体结构以及与四种结核病候选药物（包括 SQ109（处于 2b-3 期临床试验）的复合物）的晶体结构。 MmpL3 由周质孔结构域和十二螺旋跨膜结构域组成。位于该结构域中心的两个天冬氨酸-酪氨酸对似乎是质子易位的关键促进剂。 SQ109、AU1235、ICA38 和利莫那班在跨膜区域内结合并破坏这些 Asp-Tyr 对。这一结构数据将极大地推进 MmpL3 抑制剂作为新型结核病药物的开发。
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.