7C2M

Crystal structure of mycolic acid transporter MmpL3 from Mycobacterium smegmatis complexed with NITD-349

Summary for 7C2M

• Entry DOI: 10.2210/pdb7c2m/pdb
• Descriptor: Chimera of drug exporters of the RND superfamily-like protein and Endolysin, N-(4,4-dimethylcyclohexyl)-4,6-bis(fluoranyl)-1H-indole-2-carboxamide, alpha-D-glucopyranosyl 6-O-dodecyl-alpha-D-glucopyranoside, ... (4 entities in total)
• Functional Keywords: membrane protein
• Biological source: Mycolicibacterium smegmatis MC2 155; More
• Total number of polymer chains: 1
• Total formula weight: 106246.23

Authors

Zhang, B.,Yang, X.,Hu, T.,Rao, Z. (deposition date: 2020-05-08, release date: 2020-12-02, Last modification date: 2023-11-29)

Primary citation

Yang, X.,Hu, T.,Yang, X.,Xu, W.,Yang, H.,Guddat, L.W.,Zhang, B.,Rao, Z.
Structural Basis for the Inhibition of Mycobacterial MmpL3 by NITD-349 and SPIRO.
J.Mol.Biol., 432:4426-4434, 2020

PubMed Abstract: Novel antitubercular agents are urgently needed to combat the emergence of global drug resistance to human tuberculosis. Mycobacterial membrane protein Large 3 (MmpL3) is a promising drug target because its activity is essential and required for cell-wall biosynthesis. Several classes of MmpL3 inhibitors have been developed against Mycobacterium tuberculosis (Mtb) with potent anti-tuberculosis activity. These include the drug candidate SQ109, which has progressed to phase IIb/III clinical trials. Here, we have determined the crystal structures of MmpL3 in complex with NITD-349 and SPIRO. Both inhibitors bind deep in the central channel of transmembrane domain and cause conformational changes to the protein. The amide nitrogen and indole nitrogen of NITD-349 and the piperidine nitrogen of SPIRO interact and clamp Asp645. Structural analysis of the two structures reveals that these inhibitors target the proton relay pathway to block the activity of MmpL3. The findings presented here enrich our understanding of the binding modes of MmpL3 inhibitors and provide directions to enable further rational drug design targeting MmpL3.

PubMed: 32512002
DOI: 10.1016/j.jmb.2020.05.019

Experimental method

X-RAY DIFFRACTION (3.1 Å)