7c2n

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

spinqualitylabelsall models 7c2n, resolution 2.82Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7c2n is a 1 chain structure with sequence from Enterobacteria phage RB59 and Mycolicibacterium smegmatis MC2 155. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.82Å Ligands: FG0, L6T, MHA Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function MMPL3_MYCS2 Transports trehalose monomycolate (TMM) to the cell wall (PubMed:31239378, PubMed:22520756, PubMed:28698380). Flips TMM across the inner membrane. Membrane potential is not required for this function (PubMed:28698380). Transports probably phosphatidylethanolamine (PE) as well. Binds specifically both TMM and PE, but not trehalose dimycolate (TDM). Binds also diacylglycerol (DAG) and other phospholipids, including phosphatidylglycerol (PG), phosphatidylinositol (PI), and cardiolipin (CDL) (PubMed:31113875). Contributes to membrane potential, cell wall composition, antibiotic susceptibility and fitness (PubMed:28703701). Publication Abstract from PubMed 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. Structural Basis for the Inhibition of Mycobacterial MmpL3 by NITD-349 and SPIRO.,Yang X, Hu T, Yang X, Xu W, Yang H, Guddat LW, Zhang B, Rao Z J Mol Biol. 2020 Jul 24;432(16):4426-4434. doi: 10.1016/j.jmb.2020.05.019. Epub, 2020 Jun 6. PMID:32512002 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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