6AJH

Crystal structure of mycolic acid transporter MmpL3 from Mycobacterium smegmatis complexed with AU1235

6AJH の概要

• エントリーDOI: 10.2210/pdb6ajh/pdb
• 分子名称: Drug exporters of the RND superfamily-like protein,Endolysin, 1-(2-adamantyl)-3-[2,3,4-tris(fluoranyl)phenyl]urea, alpha-D-glucopyranosyl 6-O-dodecyl-alpha-D-glucopyranoside, ... (4 entities in total)
• 機能のキーワード: membrane protein, transporter, rnd family, cell wall biosynthesis, drug target, hydrolase
• 由来する生物種: Mycobacterium smegmatis (strain ATCC 700084 / mc(2)155); 詳細
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 107455.51

構造登録者

Zhang, B.,Li, J.,Yang, X.L.,Wu, L.J.,Yang, H.T.,Rao, Z.H. (登録日: 2018-08-27, 公開日: 2018-12-26, 最終更新日: 2023-11-22)

主引用文献

Zhang, B.,Li, J.,Yang, X.,Wu, L.,Zhang, J.,Yang, Y.,Zhao, Y.,Zhang, L.,Yang, X.,Yang, X.,Cheng, X.,Liu, Z.,Jiang, B.,Jiang, H.,Guddat, L.W.,Yang, H.,Rao, Z.
Crystal Structures of Membrane Transporter MmpL3, an Anti-TB Drug Target.
Cell, 176:636-648.e13, 2019

PubMed 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.

PubMed: 30682372
DOI: 10.1016/j.cell.2019.01.003

実験手法

X-RAY DIFFRACTION (2.818 Å)