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| | ==Crystal structure of Antigen 85C-C209S mutant== | | ==Crystal structure of Antigen 85C-C209S mutant== |
| - | <StructureSection load='4mql' size='340' side='right' caption='[[4mql]], [[Resolution|resolution]] 1.30Å' scene=''> | + | <StructureSection load='4mql' size='340' side='right'caption='[[4mql]], [[Resolution|resolution]] 1.30Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4mql]] is a 1 chain structure with sequence from [http://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=4MQL OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4MQL FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4mql]] 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=4MQL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4MQL FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BTB:2-[BIS-(2-HYDROXY-ETHYL)-AMINO]-2-HYDROXYMETHYL-PROPANE-1,3-DIOL'>BTB</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BTB:2-[BIS-(2-HYDROXY-ETHYL)-AMINO]-2-HYDROXYMETHYL-PROPANE-1,3-DIOL'>BTB</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4mqm|4mqm]]</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=4mql FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4mql OCA], [https://pdbe.org/4mql PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4mql RCSB], [https://www.ebi.ac.uk/pdbsum/4mql PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4mql ProSAT]</span></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">fbpC, mpt45, Rv0129c, MT0137, MTCI5.03c ([http://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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4mql FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4mql OCA], [http://pdbe.org/4mql PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4mql RCSB], [http://www.ebi.ac.uk/pdbsum/4mql PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4mql ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/A85C_MYCTU A85C_MYCTU]] The antigen 85 proteins (FbpA, FbpB, FbpC) are responsible for the high affinity of mycobacteria to fibronectin, a large adhesive glycoprotein, which facilitates the attachment of M.tuberculosis to murine alveolar macrophages (AMs). They also help to maintain the integrity of the cell wall by catalyzing the transfer of mycolic acids to cell wall arabinogalactan and through the synthesis of alpha,alpha-trehalose dimycolate (TDM, cord factor). They catalyze the transfer of a mycoloyl residue from one molecule of alpha,alpha-trehalose monomycolate (TMM) to another TMM, leading to the formation of TDM.<ref>PMID:1830294</ref> <ref>PMID:9162010</ref> | + | [https://www.uniprot.org/uniprot/A85C_MYCTU A85C_MYCTU] The antigen 85 proteins (FbpA, FbpB, FbpC) are responsible for the high affinity of mycobacteria to fibronectin, a large adhesive glycoprotein, which facilitates the attachment of M.tuberculosis to murine alveolar macrophages (AMs). They also help to maintain the integrity of the cell wall by catalyzing the transfer of mycolic acids to cell wall arabinogalactan and through the synthesis of alpha,alpha-trehalose dimycolate (TDM, cord factor). They catalyze the transfer of a mycoloyl residue from one molecule of alpha,alpha-trehalose monomycolate (TMM) to another TMM, leading to the formation of TDM.<ref>PMID:1830294</ref> <ref>PMID:9162010</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | ==See Also== | | ==See Also== |
| - | *[[Antigen 85|Antigen 85]] | + | *[[Antigen 85 3D structures|Antigen 85 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Boucau, J]] | + | [[Category: Large Structures]] |
| - | [[Category: Favrot, L]] | + | [[Category: Mycobacterium tuberculosis]] |
| - | [[Category: Grzegorzewicz, A E]] | + | [[Category: Boucau J]] |
| - | [[Category: Isailovic, D]] | + | [[Category: Favrot L]] |
| - | [[Category: Jackson, M]] | + | [[Category: Grzegorzewicz AE]] |
| - | [[Category: Lajiness, D H]] | + | [[Category: Isailovic D]] |
| - | [[Category: Marvin, R K]] | + | [[Category: Jackson M]] |
| - | [[Category: Ronning, D R]] | + | [[Category: Lajiness DH]] |
| - | [[Category: Acyltransferase]] | + | [[Category: Marvin RK]] |
| - | [[Category: Transferase]] | + | [[Category: Ronning DR]] |
| Structural highlights
Function
A85C_MYCTU The antigen 85 proteins (FbpA, FbpB, FbpC) are responsible for the high affinity of mycobacteria to fibronectin, a large adhesive glycoprotein, which facilitates the attachment of M.tuberculosis to murine alveolar macrophages (AMs). They also help to maintain the integrity of the cell wall by catalyzing the transfer of mycolic acids to cell wall arabinogalactan and through the synthesis of alpha,alpha-trehalose dimycolate (TDM, cord factor). They catalyze the transfer of a mycoloyl residue from one molecule of alpha,alpha-trehalose monomycolate (TMM) to another TMM, leading to the formation of TDM.[1] [2]
Publication Abstract from PubMed
The increasing prevalence of drug-resistant tuberculosis highlights the need for identifying new antitubercular drugs that can treat these infections. The antigen 85 (Ag85) complex has emerged as an intriguing mycobacterial drug target due to its central role in synthesizing major components of the inner and outer leaflets of the mycobacterial outer membrane. Here we identify ebselen (EBS) as a potent inhibitor of the Mycobacterium tuberculosis Ag85 complex. Mass spectrometry data show that EBS binds covalently to a cysteine residue (C209) located near the Ag85C active site. The crystal structure of Ag85C in the presence of EBS shows that C209 modification restructures the active site, thereby disrupting the hydrogen-bonded network within the active site that is essential for enzymatic activity. C209 mutations display marked decreases in enzymatic activity. These data suggest that compounds using this mechanism of action will strongly inhibit the Ag85 complex and minimize the selection of drug resistance.
Mechanism of inhibition of Mycobacterium tuberculosis antigen 85 by ebselen.,Favrot L, Grzegorzewicz AE, Lajiness DH, Marvin RK, Boucau J, Isailovic D, Jackson M, Ronning DR Nat Commun. 2013;4:2748. doi: 10.1038/ncomms3748. PMID:24193546[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Abou-Zeid C, Garbe T, Lathigra R, Wiker HG, Harboe M, Rook GA, Young DB. Genetic and immunological analysis of Mycobacterium tuberculosis fibronectin-binding proteins. Infect Immun. 1991 Aug;59(8):2712-8. PMID:1830294
- ↑ Belisle JT, Vissa VD, Sievert T, Takayama K, Brennan PJ, Besra GS. Role of the major antigen of Mycobacterium tuberculosis in cell wall biogenesis. Science. 1997 May 30;276(5317):1420-2. PMID:9162010
- ↑ Favrot L, Grzegorzewicz AE, Lajiness DH, Marvin RK, Boucau J, Isailovic D, Jackson M, Ronning DR. Mechanism of inhibition of Mycobacterium tuberculosis antigen 85 by ebselen. Nat Commun. 2013;4:2748. doi: 10.1038/ncomms3748. PMID:24193546 doi:http://dx.doi.org/10.1038/ncomms3748
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