7nvh

From Proteopedia

(Difference between revisions)

Revision as of 10:07, 21 December 2022

Cryo-EM structure of the mycolic acid transporter MmpL3 from M. tuberculosis

Structural highlights

7nvh is a 1 chain structure with sequence from Mycobacterium tuberculosis. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

MMPL3_MYCTU Transports trehalose monomycolate (TMM) to the cell wall. Flips TMM across the inner membrane (PubMed:22252828, PubMed:22344175). Membrane potential is not required for this function. 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). Contributes to membrane potential, cell wall composition, antibiotic susceptibility and fitness (By similarity). Could also be part of a heme-iron acquisition system (PubMed:21383189).[UniProtKB:A0QP27]^[1] ^[2] ^[3] Is the target of the antitubercular drug SQ109.^[4]

Publication Abstract from PubMed

Tuberculosis (TB) is the leading cause of death from a single infectious agent and in 2019 an estimated 10 million people worldwide contracted the disease. Although treatments for TB exist, continual emergence of drug-resistant variants necessitates urgent development of novel antituberculars. An important new target is the lipid transporter MmpL3, which is required for construction of the unique cell envelope that shields Mycobacterium tuberculosis (Mtb) from the immune system. However, a structural understanding of the mutations in Mtb MmpL3 that confer resistance to the many preclinical leads is lacking, hampering efforts to circumvent resistance mechanisms. Here, we present the cryoelectron microscopy structure of Mtb MmpL3 and use it to comprehensively analyze the mutational landscape of drug resistance. Our data provide a rational explanation for resistance variants local to the central drug binding site, and also highlight a potential alternative route to resistance operating within the periplasmic domain.

Cryo-EM structure and resistance landscape of M. tuberculosis MmpL3: An emergent therapeutic target.,Adams O, Deme JC, Parker JL, Fowler PW, Lea SM, Newstead S Structure. 2021 Jun 28. pii: S0969-2126(21)00217-3. doi:, 10.1016/j.str.2021.06.013. PMID:34242558^[5]

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

References

↑ Tahlan K, Wilson R, Kastrinsky DB, Arora K, Nair V, Fischer E, Barnes SW, Walker JR, Alland D, Barry CE 3rd, Boshoff HI. SQ109 targets MmpL3, a membrane transporter of trehalose monomycolate involved in mycolic acid donation to the cell wall core of Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2012 Apr;56(4):1797-809. doi: 10.1128/AAC.05708-11. , Epub 2012 Jan 17. PMID:22252828 doi:http://dx.doi.org/10.1128/AAC.05708-11
↑ Grzegorzewicz AE, Pham H, Gundi VA, Scherman MS, North EJ, Hess T, Jones V, Gruppo V, Born SE, Kordulakova J, Chavadi SS, Morisseau C, Lenaerts AJ, Lee RE, McNeil MR, Jackson M. Inhibition of mycolic acid transport across the Mycobacterium tuberculosis plasma membrane. Nat Chem Biol. 2012 Feb 19;8(4):334-41. doi: 10.1038/nchembio.794. PMID:22344175 doi:http://dx.doi.org/10.1038/nchembio.794
↑ Tullius MV, Harmston CA, Owens CP, Chim N, Morse RP, McMath LM, Iniguez A, Kimmey JM, Sawaya MR, Whitelegge JP, Horwitz MA, Goulding CW. Discovery and characterization of a unique mycobacterial heme acquisition system. Proc Natl Acad Sci U S A. 2011 Mar 7. PMID:21383189 doi:10.1073/pnas.1009516108
↑ Tahlan K, Wilson R, Kastrinsky DB, Arora K, Nair V, Fischer E, Barnes SW, Walker JR, Alland D, Barry CE 3rd, Boshoff HI. SQ109 targets MmpL3, a membrane transporter of trehalose monomycolate involved in mycolic acid donation to the cell wall core of Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2012 Apr;56(4):1797-809. doi: 10.1128/AAC.05708-11. , Epub 2012 Jan 17. PMID:22252828 doi:http://dx.doi.org/10.1128/AAC.05708-11
↑ Adams O, Deme JC, Parker JL, Fowler PW, Lea SM, Newstead S. Cryo-EM structure and resistance landscape of M. tuberculosis MmpL3: An emergent therapeutic target. Structure. 2021 Jun 28. pii: S0969-2126(21)00217-3. doi:, 10.1016/j.str.2021.06.013. PMID:34242558 doi:http://dx.doi.org/10.1016/j.str.2021.06.013

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/7nvh"

@@ Line 3: / Line 3: @@
 <StructureSection load='7nvh' size='340' side='right'caption='[[7nvh]], [[Resolution|resolution]] 3.02&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[7nvh]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/"bacillus_tuberculosis"_(zopf_1883)_klein_1884 "bacillus tuberculosis" (zopf 1883) klein 1884]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7NVH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7NVH FirstGlance]. <br>
+<table><tr><td colspan='2'>[[7nvh]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7NVH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7NVH FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AV0:2-decyl-2-{[(4-O-alpha-D-glucopyranosyl-beta-D-glucopyranosyl)oxy]methyl}dodecyl+4-O-alpha-D-glucopyranosyl-beta-D-glucopyranoside'>AV0</scene></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Rv0206c ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1773 "Bacillus tuberculosis" (Zopf 1883) Klein 1884])</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=7nvh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7nvh OCA], [https://pdbe.org/7nvh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7nvh RCSB], [https://www.ebi.ac.uk/pdbsum/7nvh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7nvh ProSAT]</span></td></tr>
 </table>
+== Function ==
+[https://www.uniprot.org/uniprot/MMPL3_MYCTU MMPL3_MYCTU] Transports trehalose monomycolate (TMM) to the cell wall. Flips TMM across the inner membrane (PubMed:22252828, PubMed:22344175). Membrane potential is not required for this function. 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). Contributes to membrane potential, cell wall composition, antibiotic susceptibility and fitness (By similarity). Could also be part of a heme-iron acquisition system (PubMed:21383189).[UniProtKB:A0QP27]<ref>PMID:22252828</ref> <ref>PMID:22344175</ref> <ref>PMID:21383189</ref>   Is the target of the antitubercular drug SQ109.<ref>PMID:22252828</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 22: / Line 23: @@
 </StructureSection>
 [[Category: Large Structures]]
-[[Category: Adams, O]]
+[[Category: Mycobacterium tuberculosis]]
-[[Category: Deme, J C]]
+[[Category: Adams O]]
-[[Category: Lea, S M]]
+[[Category: Deme JC]]
-[[Category: Newstead, S]]
+[[Category: Lea SM]]
-[[Category: Parker, J L]]
+[[Category: Newstead S]]
-[[Category: Membrane protein]]
+[[Category: Parker JL]]
-[[Category: Transporter]]

7nvh

From Proteopedia

Revision as of 10:07, 21 December 2022

Cryo-EM structure of the mycolic acid transporter MmpL3 from M. tuberculosis

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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