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| | ==Crystal structure of Ag85C bound to cyclophostin 8beta inhibitor== | | ==Crystal structure of Ag85C bound to cyclophostin 8beta inhibitor== |
| - | <StructureSection load='5ocj' size='340' side='right' caption='[[5ocj]], [[Resolution|resolution]] 1.80Å' scene=''> | + | <StructureSection load='5ocj' size='340' side='right'caption='[[5ocj]], [[Resolution|resolution]] 1.80Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5ocj]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5OCJ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5OCJ FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5ocj]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis_H37Rv Mycobacterium tuberculosis H37Rv]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5OCJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5OCJ FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=9SW:methoxy-[(3~{R})-3-[(2~{R})-1-methoxy-1,3-bis(oxidanylidene)butan-2-yl]pentadecyl]phosphinic+acid'>9SW</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</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]] 1.8Å</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=5ocj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ocj OCA], [http://pdbe.org/5ocj PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ocj RCSB], [http://www.ebi.ac.uk/pdbsum/5ocj PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ocj ProSAT]</span></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=9SW:methoxy-[(3~{R})-3-[(2~{R})-1-methoxy-1,3-bis(oxidanylidene)butan-2-yl]pentadecyl]phosphinic+acid'>9SW</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene></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=5ocj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ocj OCA], [https://pdbe.org/5ocj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ocj RCSB], [https://www.ebi.ac.uk/pdbsum/5ocj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ocj 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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| | </div> | | </div> |
| | <div class="pdbe-citations 5ocj" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 5ocj" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Antigen 85 3D structures|Antigen 85 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Blaise, M]] | + | [[Category: Large Structures]] |
| - | [[Category: Canaan, S]] | + | [[Category: Mycobacterium tuberculosis H37Rv]] |
| - | [[Category: Cavalier, J F]] | + | [[Category: Blaise M]] |
| - | [[Category: Kremer, L]]
| + | [[Category: Canaan S]] |
| - | [[Category: Nguyen, P C]]
| + | [[Category: Cavalier JF]] |
| - | [[Category: Richard, M]]
| + | [[Category: Kremer L]] |
| - | [[Category: Spilling, C D]] | + | [[Category: Nguyen PC]] |
| - | [[Category: Viljoen, A]] | + | [[Category: Richard M]] |
| - | [[Category: Ag85c]] | + | [[Category: Spilling CD]] |
| - | [[Category: Mycolicate]] | + | [[Category: Viljoen A]] |
| - | [[Category: Mycomembrane]] | + | |
| - | [[Category: Tdm]] | + | |
| - | [[Category: Tmm]] | + | |
| - | [[Category: Transferase]]
| + | |
| 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
An increasing prevalence of cases of drug-resistant tuberculosis requires the development of more efficacious chemotherapies. We previously reported the discovery of a new class of Cyclipostins and Cyclophostin (CyC) analogs exhibiting potent activity against Mycobacterium tuberculosis both in vitro and in infected macrophages. Competitive labeling/enrichment assays combined with MS have identified several serine or cysteine enzymes in lipid and cell wall metabolism as putative targets of these CyC compounds. These targets included members of the antigen 85 (Ag85) complex (i.e. Ag85A, Ag85B, and Ag85C), responsible for biosynthesis of trehalose dimycolate (TDM) and mycolylation of arabinogalactan. Herein, we used biochemical and structural approaches to validate the Ag85 complex as a pharmacological target of the CyC analogs. We found that CyC7beta, CyC8beta, and CyC17 bind covalently to the catalytic Ser124 residue in Ag85C, inhibit mycolyltransferase activity, i.e. the transfer of a fatty acid molecule onto trehalose, and reduce triacylglycerol synthase activity, a property previously attributed to Ag85A. Supporting these results, an X-ray structure of Ag85C in complex with CyC8beta disclosed that this inhibitor occupies Ag85C's substrate-binding pocket. Importantly, metabolic labeling of M. tuberculosis cultures revealed that the CyC compounds impair both TDM synthesis and mycolylation of arabinogalactan. Overall, our study provides compelling evidence that CyC analogs can inhibit the activity of the Ag85 complex in vitro and in mycobacteria, opening the door to a new strategy for inhibiting Ag85. The high-resolution crystal structure obtained will further guide the rational optimization of new CyC scaffolds with greater specificity and potency against M. tuberculosis.
Cyclipostins and Cyclophostin analogs inhibit the antigen 85C from Mycobacterium tuberculosis both in vitro and in vivo.,Viljoen A, Richard M, Nguyen PC, Fourquet P, Camoin L, Paudal RR, Gnawali GR, Spilling CD, Cavalier JF, Canaan S, Blaise M, Kremer L J Biol Chem. 2018 Jan 4. pii: RA117.000760. doi: 10.1074/jbc.RA117.000760. PMID:29301937[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
- ↑ Viljoen A, Richard M, Nguyen PC, Fourquet P, Camoin L, Paudal RR, Gnawali GR, Spilling CD, Cavalier JF, Canaan S, Blaise M, Kremer L. Cyclipostins and Cyclophostin analogs inhibit the antigen 85C from Mycobacterium tuberculosis both in vitro and in vivo. J Biol Chem. 2018 Jan 4. pii: RA117.000760. doi: 10.1074/jbc.RA117.000760. PMID:29301937 doi:http://dx.doi.org/10.1074/jbc.RA117.000760
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