7c2m

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

Structural highlights

7c2m 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 3.1Å
Ligands:, ,
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).[1] [2] [3] [4] [5]

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[6]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

  1. ↑ Varela C, Rittmann D, Singh A, Krumbach K, Bhatt K, Eggeling L, Besra GS, Bhatt A. MmpL genes are associated with mycolic acid metabolism in mycobacteria and corynebacteria. Chem Biol. 2012 Apr 20;19(4):498-506. doi: 10.1016/j.chembiol.2012.03.006. PMID:22520756 doi:http://dx.doi.org/10.1016/j.chembiol.2012.03.006
  2. ↑ Xu Z, Meshcheryakov VA, Poce G, Chng SS. MmpL3 is the flippase for mycolic acids in mycobacteria. Proc Natl Acad Sci U S A. 2017 Jul 25;114(30):7993-7998. doi:, 10.1073/pnas.1700062114. Epub 2017 Jul 11. PMID:28698380 doi:http://dx.doi.org/10.1073/pnas.1700062114
  3. ↑ McNeil MB, Dennison D, Parish T. Mutations in MmpL3 alter membrane potential, hydrophobicity and antibiotic susceptibility in Mycobacterium smegmatis. Microbiology (Reading). 2017 Jul;163(7):1065-1070. doi: 10.1099/mic.0.000498., Epub 2017 Jul 21. PMID:28703701 doi:http://dx.doi.org/10.1099/mic.0.000498
  4. ↑ Su CC, Klenotic PA, Bolla JR, Purdy GE, Robinson CV, Yu EW. MmpL3 is a lipid transporter that binds trehalose monomycolate and phosphatidylethanolamine. Proc Natl Acad Sci U S A. 2019 May 21. pii: 1901346116. doi:, 10.1073/pnas.1901346116. PMID:31113875 doi:http://dx.doi.org/10.1073/pnas.1901346116
  5. ↑ Fay A, Czudnochowski N, Rock JM, Johnson JR, Krogan NJ, Rosenberg O, Glickman MS. Two Accessory Proteins Govern MmpL3 Mycolic Acid Transport in Mycobacteria. mBio. 2019 Jun 25;10(3). pii: mBio.00850-19. doi: 10.1128/mBio.00850-19. PMID:31239378 doi:http://dx.doi.org/10.1128/mBio.00850-19
  6. ↑ Yang X, Hu T, Yang X, Xu W, Yang H, Guddat LW, Zhang B, Rao Z. Structural Basis for the Inhibition of Mycobacterial MmpL3 by NITD-349 and SPIRO. J Mol Biol. 2020 Jul 24;432(16):4426-4434. doi: 10.1016/j.jmb.2020.05.019. Epub, 2020 Jun 6. PMID:32512002 doi:http://dx.doi.org/10.1016/j.jmb.2020.05.019

7c2m, resolution 3.10Å

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