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

IF 45.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell Pub Date : 2019-01-24 DOI:10.1016/j.cell.2019.01.003

Bing Zhang, Jun Li, Xiaolin Yang, Lijie Wu, Jia Zhang, Yang Yang, Yao Zhao, Lu Zhang, Xiuna Yang, Xiaobao Yang, Xi Cheng, Zhijie Liu, Biao Jiang, Hualiang Jiang, Luke W Guddat, Haitao Yang, Zihe Rao

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引用次数: 147

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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抗结核药物靶点膜转运蛋白MmpL3的晶体结构

尽管为发现根除结核病的高效治疗方法作出了大量努力，但结核病仍然是对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关注。分枝杆菌大膜蛋白(Mycobacterial membrane protein Large, MmpLs)在输送脂质、聚合物和免疫调节剂中起着至关重要的作用，也可以挤出治疗药物，是近年来出现的最重要的治疗药物靶点之一。本文报道了分枝杆菌MmpL3单独和与四种结核病候选药物(包括SQ109)联合使用的晶体结构(处于2b-3期临床试验中)。MmpL3由质周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Asp-Tyr对似乎是质子易位的关键促进因子。SQ109、AU1235、ICA38和利莫那班在跨膜区域结合并破坏这些Asp-Tyr对。这一结构数据将极大地推动MmpL3抑制剂作为新型结核病药物的开发。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell 生物-生化与分子生物学

CiteScore

110.00

自引率

0.80%

发文量

396

审稿时长

2 months

期刊介绍： Cells is an international, peer-reviewed, open access journal that focuses on cell biology, molecular biology, and biophysics. It is affiliated with several societies, including the Spanish Society for Biochemistry and Molecular Biology (SEBBM), Nordic Autophagy Society (NAS), Spanish Society of Hematology and Hemotherapy (SEHH), and Society for Regenerative Medicine (Russian Federation) (RPO). The journal publishes research findings of significant importance in various areas of experimental biology, such as cell biology, molecular biology, neuroscience, immunology, virology, microbiology, cancer, human genetics, systems biology, signaling, and disease mechanisms and therapeutics. The primary criterion for considering papers is whether the results contribute to significant conceptual advances or raise thought-provoking questions and hypotheses related to interesting and important biological inquiries. In addition to primary research articles presented in four formats, Cells also features review and opinion articles in its "leading edge" section, discussing recent research advancements and topics of interest to its wide readership.