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==Crystal structure of mycolic acid transporter MmpL3 from Mycobacterium smegmatis==
==Crystal structure of mycolic acid transporter MmpL3 from Mycobacterium smegmatis==
<StructureSection load='6ajf' size='340' side='right' caption='[[6ajf]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
<StructureSection load='6ajf' size='340' side='right'caption='[[6ajf]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[6ajf]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Bpt4 Bpt4]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6AJF OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6AJF FirstGlance]. <br>
<table><tr><td colspan='2'>[[6ajf]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_virus_T4 Escherichia virus T4] and [https://en.wikipedia.org/wiki/Mycolicibacterium_smegmatis_MC2_155 Mycolicibacterium smegmatis MC2 155]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6AJF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6AJF FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=L6T:alpha-D-glucopyranosyl+6-O-dodecyl-alpha-D-glucopyranoside'>L6T</scene>, <scene name='pdbligand=MHA:(CARBAMOYLMETHYL-CARBOXYMETHYL-AMINO)-ACETIC+ACID'>MHA</scene></td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.698&#8491;</td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">e, T4Tp126 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10665 BPT4])</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=L6T:alpha-D-glucopyranosyl+6-O-dodecyl-alpha-D-glucopyranoside'>L6T</scene>, <scene name='pdbligand=MHA:(CARBAMOYLMETHYL-CARBOXYMETHYL-AMINO)-ACETIC+ACID'>MHA</scene></td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Lysozyme Lysozyme], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.2.1.17 3.2.1.17] </span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6ajf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ajf OCA], [https://pdbe.org/6ajf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6ajf RCSB], [https://www.ebi.ac.uk/pdbsum/6ajf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6ajf ProSAT]</span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6ajf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ajf OCA], [http://pdbe.org/6ajf PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ajf RCSB], [http://www.ebi.ac.uk/pdbsum/6ajf PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ajf ProSAT]</span></td></tr>
</table>
</table>
<div style="background-color:#fffaf0;">
== Function ==
== Publication Abstract from PubMed ==
[https://www.uniprot.org/uniprot/D9IEF7_BPT4 D9IEF7_BPT4] [https://www.uniprot.org/uniprot/MMPL3_MYCS2 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).<ref>PMID:22520756</ref> <ref>PMID:28698380</ref> <ref>PMID:28703701</ref> <ref>PMID:31113875</ref> <ref>PMID:31239378</ref>  
Despite intensive efforts to discover highly effective treatments to eradicate tuberculosis (TB), it remains as a major threat to global human health. For this reason, new TB drugs directed toward new targets are highly coveted. MmpLs (Mycobacterial membrane proteins Large), which play crucial roles in transporting lipids, polymers and immunomodulators and which also extrude therapeutic drugs, are among the most important therapeutic drug targets to emerge in recent times. Here, crystal structures of mycobacterial MmpL3 alone and in complex with four TB drug candidates, including SQ109 (in Phase 2b-3 clinical trials), are reported. MmpL3 consists of a periplasmic pore domain and a twelve-helix transmembrane domain. Two Asp-Tyr pairs centrally located in this domain appear to be key facilitators of proton-translocation. SQ109, AU1235, ICA38, and rimonabant bind inside the transmembrane region and disrupt these Asp-Tyr pairs. This structural data will greatly advance the development of MmpL3 inhibitors as new TB drugs.
 
Crystal Structures of Membrane Transporter MmpL3, an Anti-TB Drug Target.,Zhang B, Li J, Yang X, Wu L, Zhang J, Yang Y, Zhao Y, Zhang L, Yang X, Yang X, Cheng X, Liu Z, Jiang B, Jiang H, Guddat LW, Yang H, Rao Z Cell. 2019 Jan 24;176(3):636-648.e13. doi: 10.1016/j.cell.2019.01.003. PMID:30682372<ref>PMID:30682372</ref>
 
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6ajf" style="background-color:#fffaf0;"></div>
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Bpt4]]
[[Category: Escherichia virus T4]]
[[Category: Lysozyme]]
[[Category: Large Structures]]
[[Category: Li, J]]
[[Category: Mycolicibacterium smegmatis MC2 155]]
[[Category: Rao, Z H]]
[[Category: Li J]]
[[Category: Wu, L J]]
[[Category: Rao ZH]]
[[Category: Yang, H T]]
[[Category: Wu LJ]]
[[Category: Yang, X L]]
[[Category: Yang HT]]
[[Category: Zhang, B]]
[[Category: Yang XL]]
[[Category: Cell wall biosynthesis]]
[[Category: Zhang B]]
[[Category: Drug target]]
[[Category: Hydrolase]]
[[Category: Membrane protein]]
[[Category: Rnd family]]
[[Category: Transporter]]

Latest revision as of 13:32, 27 March 2024

Crystal structure of mycolic acid transporter MmpL3 from Mycobacterium smegmatisCrystal structure of mycolic acid transporter MmpL3 from Mycobacterium smegmatis

Structural highlights

6ajf is a 1 chain structure with sequence from Escherichia virus T4 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 2.698Å
Ligands:,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

D9IEF7_BPT4 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]

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

6ajf, resolution 2.70Å

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