7WNX

Cryo-EM structure of Mycobacterium smegmatis MmpL3 complexed with ST004 in lipid nanodiscs

7WNX の概要

• エントリーDOI: 10.2210/pdb7wnx/pdb
• EMDBエントリー: 32634
• 分子名称: Trehalose monomycolate exporter MmpL3, N-[2-(2-adamantylamino)ethyl]-1-[2,4-bis(fluoranyl)phenyl]-5-(4-chlorophenyl)-4-methyl-pyrazole-3-carboxamide (2 entities in total)
• 機能のキーワード: drug target, novel compound, mycobacterium tuberculosis, membrane protein
• 由来する生物種: Mycolicibacterium smegmatis MC2 155
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 110581.81

構造登録者

Zhang, B.,Hu, T.,Yang, X.,Liu, F.,Rao, Z. (登録日: 2022-01-20, 公開日: 2022-08-03, 最終更新日: 2024-04-10)

主引用文献

Hu, T.,Yang, X.,Liu, F.,Sun, S.,Xiong, Z.,Liang, J.,Yang, X.,Wang, H.,Yang, X.,Guddat, L.W.,Yang, H.,Rao, Z.,Zhang, B.
Structure-based design of anti-mycobacterial drug leads that target the mycolic acid transporter MmpL3.
Structure, 30:1395-1402.e4, 2022

PubMed Abstract: New anti-tubercular agents are urgently needed to address the emerging threat of drug resistance to human tuberculosis. Here, we have used structure-assisted methods to develop compounds that target mycobacterial membrane protein large 3 (MmpL3). MmpL3 is essential for the transport of mycolic acids, an important cell-wall component of mycobacteria. We prepared compounds that potently inhibit the growth of Mycobacterium tuberculosis (Mtb) and other mycobacteria in cell culture. The cryoelectron microscopy (cryo-EM) structure of mycobacterial MmpL3 in complex with one of these compounds (ST004) was determined using lipid nanodiscs at an overall resolution of 3.36 Å. The structure reveals the binding mode of ST004 to MmpL3, with the S4 and S5 subsites of the inhibitor-binding pocket in the proton translocation channel playing vital roles. These data are a promising starting point for the development of anti-tuberculosis drugs that target MmpL3.

PubMed: 35981536
DOI: 10.1016/j.str.2022.07.009

実験手法

ELECTRON MICROSCOPY (3.36 Å)