6ajg

From Proteopedia

(Difference between revisions)

Current revision

Crystal structure of mycolic acid transporter MmpL3 from Mycobacterium smegmatis complexed with SQ109

Structural highlights

6ajg 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 2.604Å
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]

Publication Abstract from PubMed

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^[6]

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

References

↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ 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. Crystal Structures of Membrane Transporter MmpL3, an Anti-TB Drug Target. Cell. 2019 Jan 24;176(3):636-648.e13. doi: 10.1016/j.cell.2019.01.003. PMID:30682372 doi:http://dx.doi.org/10.1016/j.cell.2019.01.003

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6ajg"

@@ Line 1: / Line 1: @@
 ==Crystal structure of mycolic acid transporter MmpL3 from Mycobacterium smegmatis complexed with SQ109==
-<StructureSection load='6ajg' size='340' side='right' caption='[[6ajg]], [[Resolution|resolution]] 2.60&Aring;' scene=''>
+<StructureSection load='6ajg' size='340' side='right'caption='[[6ajg]], [[Resolution|resolution]] 2.60&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6ajg]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6AJG OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6AJG FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6ajg]] 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=6AJG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6AJG FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3RX:N-[(2E)-3,7-DIMETHYLOCTA-2,6-DIEN-1-YL]-N-[(1R,3S,5R,7R)-TRICYCLO[3.3.1.1~3,7~]DEC-2-YL]ETHANE-1,2-DIAMINE'>3RX</scene>, <scene name='pdbligand=LMT:DODECYL-BETA-D-MALTOSIDE'>LMT</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]] 2.604&#8491;</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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3RX:N-[(2E)-3,7-DIMETHYLOCTA-2,6-DIEN-1-YL]-N-[(1R,3S,5R,7R)-TRICYCLO[3.3.1.1~3,7~]DEC-2-YL]ETHANE-1,2-DIAMINE'>3RX</scene>, <scene name='pdbligand=LMT:DODECYL-BETA-D-MALTOSIDE'>LMT</scene>, <scene name='pdbligand=MHA:(CARBAMOYLMETHYL-CARBOXYMETHYL-AMINO)-ACETIC+ACID'>MHA</scene></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=6ajg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ajg OCA], [http://pdbe.org/6ajg PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ajg RCSB], [http://www.ebi.ac.uk/pdbsum/6ajg PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ajg ProSAT]</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=6ajg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ajg OCA], [https://pdbe.org/6ajg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6ajg RCSB], [https://www.ebi.ac.uk/pdbsum/6ajg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6ajg ProSAT]</span></td></tr>
 </table>
+== Function ==
+[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>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+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 6ajg" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
 __TOC__
 </StructureSection>
-[[Category: Lysozyme]]
+[[Category: Escherichia virus T4]]
-[[Category: Li, J]]
+[[Category: Large Structures]]
-[[Category: Rao, Z H]]
+[[Category: Mycolicibacterium smegmatis MC2 155]]
-[[Category: Wu, L J]]
+[[Category: Li J]]
-[[Category: Yang, H T]]
+[[Category: Rao ZH]]
-[[Category: Yang, X L]]
+[[Category: Wu LJ]]
-[[Category: Zhang, B]]
+[[Category: Yang HT]]
-[[Category: Cell wall biosynthesis]]
+[[Category: Yang XL]]
-[[Category: Drug target]]
+[[Category: Zhang B]]
-[[Category: Hydrolase]]
-[[Category: Membrane protein]]
-[[Category: Rnd family]]
-[[Category: Transporter]]

6ajg

From Proteopedia

Current revision

Crystal structure of mycolic acid transporter MmpL3 from Mycobacterium smegmatis complexed with SQ109

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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