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-Structure paper
タイトル | Structure-based design of anti-mycobacterial drug leads that target the mycolic acid transporter MmpL3. |
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ジャーナル・号・ページ | Structure, Vol. 30, Issue 10, Page 1395-11402.e4, Year 2022 |
掲載日 | 2022年10月6日 |
著者 | Tianyu Hu / Xiaolin Yang / Fengjiang Liu / Shan Sun / Zhiqi Xiong / Jingxi Liang / Xiaobao Yang / Haofeng Wang / Xiuna Yang / Luke W Guddat / Haitao Yang / Zihe Rao / Bing Zhang / |
PubMed 要旨 | 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 ...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. |
リンク | Structure / PubMed:35981536 |
手法 | EM (単粒子) |
解像度 | 3.36 Å |
構造データ | EMDB-32634, PDB-7wnx: |
化合物 | ChemComp-1I2: |
由来 |
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キーワード | MEMBRANE PROTEIN / drug target / novel compound / Mycobacterium tuberculosis |