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6g83
From Proteopedia
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| - | '''Unreleased structure''' | ||
| - | + | ==Crystal structure of M. tuberculosis DprE1 in complex with sPBTZ169 (sulfonylPBTZ)== | |
| + | <StructureSection load='6g83' size='340' side='right' caption='[[6g83]], [[Resolution|resolution]] 2.40Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[6g83]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6G83 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6G83 FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EQ8:[2-(4-cyclohexylsulfonylpiperazin-1-yl)-4-oxidanylidene-6-(trifluoromethyl)-1,3-benzothiazin-8-yl]-oxidanylidene-azanium'>EQ8</scene>, <scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene></td></tr> | ||
| + | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4ncr|4ncr]]</td></tr> | ||
| + | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Decaprenylphospho-beta-D-ribofuranose_2-oxidase Decaprenylphospho-beta-D-ribofuranose 2-oxidase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.98.3 1.1.98.3] </span></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=6g83 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6g83 OCA], [http://pdbe.org/6g83 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6g83 RCSB], [http://www.ebi.ac.uk/pdbsum/6g83 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6g83 ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [[http://www.uniprot.org/uniprot/DPRE1_MYCTO DPRE1_MYCTO]] Component of the DprE1-DprE2 complex that catalyzes the 2-step epimerization of decaprenyl-phospho-ribose (DPR) to decaprenyl-phospho-arabinose (DPA), a key precursor that serves as the arabinose donor required for the synthesis of cell-wall arabinans. DprE1 catalyzes the first step of epimerization, namely FAD-dependent oxidation of the C2' hydroxyl of DPR to yield the keto intermediate decaprenyl-phospho-2'-keto-D-arabinose (DPX). The intermediate DPX is then transferred to DprE2 subunit of the epimerase complex, most probably through a 'substrate channel' at the interface of DprE1-DprE2 complex. Can also use farnesyl-phosphoryl-beta-D-ribofuranose (FPR) as substrate in vitro.[UniProtKB:P9WJF1] DprE1 is a highly vulnerable and fully validated tuberculosis drug target.[UniProtKB:P9WJF1] | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Macozinone (MCZ) is a tuberculosis (TB) drug candidate that specifically targets the essential flavoenzyme DprE1 thereby blocking synthesis of the cell wall precursor decaprenyl phosphoarabinose (DPA) and provoking lysis of Mycobacterium tuberculosis As part of the MCZ back-up program we exploited structure-guided drug design to produce a new series of sulfone-containing derivatives, 2-sulphonylpiperazin 8-nitro 6-trifluoromethyl 1,3-benzothiazin-4-one, or sPBTZ. These compounds are less active than MCZ but have a better solubility profile and some derivatives display enhanced stability in microsomal assays. DprE1 was efficiently inhibited by sPBTZ and covalent adducts with the active site cysteine residue (C387) were formed. However, despite the H-bonding potential of the sulfone group no additional bonds were seen in the crystal structure of the sPBTZ-DprE1 complex with compound 11326127 as compared to MCZ. Compound 11626091, the most advanced sPBTZ, displayed good antitubercular activity in the murine model of chronic TB but was less effective than MCZ. Nonetheless, further testing of this MCZ backup compound is warranted as part of combination treatment with other TB drugs. | ||
| - | + | Structure-based drug design and characterization of sulfonyl-piperazine benzothiazinone inhibitors of DprE1 from Mycobacterium tuberculosis.,Piton J, Vocat A, Lupien A, Foo C, Riabova O, Makarov V, Cole ST Antimicrob Agents Chemother. 2018 Jul 16. pii: AAC.00681-18. doi:, 10.1128/AAC.00681-18. PMID:30012754<ref>PMID:30012754</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| - | [[Category: Cole, S | + | <div class="pdbe-citations 6g83" style="background-color:#fffaf0;"></div> |
| - | + | == References == | |
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Decaprenylphospho-beta-D-ribofuranose 2-oxidase]] | ||
| + | [[Category: Cole, S T]] | ||
[[Category: Makarov, V]] | [[Category: Makarov, V]] | ||
| + | [[Category: Piton, J]] | ||
| + | [[Category: Btz]] | ||
| + | [[Category: Complex]] | ||
| + | [[Category: Dpre1]] | ||
| + | [[Category: Inhibitor]] | ||
| + | [[Category: M. tuberculosis]] | ||
| + | [[Category: Oxidoreductase]] | ||
Revision as of 18:55, 1 August 2018
Crystal structure of M. tuberculosis DprE1 in complex with sPBTZ169 (sulfonylPBTZ)
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