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| | <StructureSection load='6za6' size='340' side='right'caption='[[6za6]], [[Resolution|resolution]] 1.80Å' scene=''> | | <StructureSection load='6za6' size='340' side='right'caption='[[6za6]], [[Resolution|resolution]] 1.80Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6za6]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Myctu Myctu]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6ZA6 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6ZA6 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6za6]] is a 4 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=6ZA6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6ZA6 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BA:BARIUM+ION'>BA</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</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]] 1.804Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">mbtI, trpE2, Rv2386c ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=83332 MYCTU])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BA:BARIUM+ION'>BA</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6za6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6za6 OCA], [http://pdbe.org/6za6 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6za6 RCSB], [http://www.ebi.ac.uk/pdbsum/6za6 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6za6 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=6za6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6za6 OCA], [https://pdbe.org/6za6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6za6 RCSB], [https://www.ebi.ac.uk/pdbsum/6za6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6za6 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/MBTI_MYCTU MBTI_MYCTU]] Mediates the production of salicylate from chorismate via an isochorismate intermediate. Presents both isochorismate synthase and isochorismate-pyruvate lyase activities. Salycilate is the starter unit in the production of the virulence-conferring salicylate-based siderophore mycobactin.<ref>PMID:16923875</ref> | + | [https://www.uniprot.org/uniprot/MBTI_MYCTU MBTI_MYCTU] Mediates the production of salicylate from chorismate via an isochorismate intermediate. Presents both isochorismate synthase and isochorismate-pyruvate lyase activities. Salycilate is the starter unit in the production of the virulence-conferring salicylate-based siderophore mycobactin.<ref>PMID:16923875</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </StructureSection> | | </StructureSection> |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Myctu]] | + | [[Category: Mycobacterium tuberculosis H37Rv]] |
| - | [[Category: Bellinzoni, M]] | + | [[Category: Bellinzoni M]] |
| - | [[Category: Meneghetti, F]] | + | [[Category: Meneghetti F]] |
| - | [[Category: Mori, M]] | + | [[Category: Mori M]] |
| - | [[Category: Villa, S]] | + | [[Category: Villa S]] |
| - | [[Category: Chorismate]]
| + | |
| - | [[Category: Isochorismate]]
| + | |
| - | [[Category: Lyase]]
| + | |
| - | [[Category: Mycobactin]]
| + | |
| - | [[Category: Salicylate]]
| + | |
| Structural highlights
Function
MBTI_MYCTU Mediates the production of salicylate from chorismate via an isochorismate intermediate. Presents both isochorismate synthase and isochorismate-pyruvate lyase activities. Salycilate is the starter unit in the production of the virulence-conferring salicylate-based siderophore mycobactin.[1]
Publication Abstract from PubMed
The Mg(2+)-dependent Mycobacterium tuberculosis salicylate synthase (MbtI) is a key enzyme involved in the biosynthesis of siderophores. Because iron is essential for the survival and pathogenicity of the microorganism, this protein constitutes an attractive target for antitubercular therapy, also considering the absence of homologous enzymes in mammals. An extension of the structure-activity relationships of our furan-based candidates allowed us to disclose the most potent competitive inhibitor known to date (10, Ki = 4 muM), which also proved effective on mycobacterial cultures. By structural studies, we characterized its unexpected Mg(2+)-independent binding mode. We also investigated the role of the Mg(2+) cofactor in catalysis, analyzing the first crystal structure of the MbtI-Mg(2+)-salicylate ternary complex. Overall, these results pave the way for the development of novel antituberculars through the rational design of improved MbtI inhibitors.
Shedding X-ray Light on the Role of Magnesium in the Activity of Mycobacterium tuberculosis Salicylate Synthase (MbtI) for Drug Design.,Mori M, Stelitano G, Gelain A, Pini E, Chiarelli LR, Sammartino JC, Poli G, Tuccinardi T, Beretta G, Porta A, Bellinzoni M, Villa S, Meneghetti F J Med Chem. 2020 Jun 25. doi: 10.1021/acs.jmedchem.0c00373. PMID:32530281[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Harrison AJ, Yu M, Gardenborg T, Middleditch M, Ramsay RJ, Baker EN, Lott JS. The structure of MbtI from Mycobacterium tuberculosis, the first enzyme in the biosynthesis of the siderophore mycobactin, reveals it to be a salicylate synthase. J Bacteriol. 2006 Sep;188(17):6081-91. PMID:16923875 doi:http://dx.doi.org/188/17/6081
- ↑ Mori M, Stelitano G, Gelain A, Pini E, Chiarelli LR, Sammartino JC, Poli G, Tuccinardi T, Beretta G, Porta A, Bellinzoni M, Villa S, Meneghetti F. Shedding X-ray Light on the Role of Magnesium in the Activity of Mycobacterium tuberculosis Salicylate Synthase (MbtI) for Drug Design. J Med Chem. 2020 Jun 25. doi: 10.1021/acs.jmedchem.0c00373. PMID:32530281 doi:http://dx.doi.org/10.1021/acs.jmedchem.0c00373
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