7WNX

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

Summary for 7WNX

• Entry DOI: 10.2210/pdb7wnx/pdb
• EMDB information: 32634
• Descriptor: 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)
• Functional Keywords: drug target, novel compound, mycobacterium tuberculosis, membrane protein
• Biological source: Mycolicibacterium smegmatis MC2 155
• Total number of polymer chains: 1
• Total formula weight: 110581.81

Authors

Zhang, B.,Hu, T.,Yang, X.,Liu, F.,Rao, Z. (deposition date: 2022-01-20, release date: 2022-08-03, Last modification date: 2024-04-10)

Primary citation

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

Experimental method

ELECTRON MICROSCOPY (3.36 Å)