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| | ==Crystal structure of M. tuberculosis DprE1 in complex with sPBTZ169 (sulfonylPBTZ)== | | ==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=''> | + | <StructureSection load='6g83' size='340' side='right'caption='[[6g83]], [[Resolution|resolution]] 2.40Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6g83]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Mycto Mycto]. 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> | + | <table><tr><td colspan='2'>[[6g83]] 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=6G83 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/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> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6g83 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6g83 OCA], [https://pdbe.org/6g83 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6g83 RCSB], [https://www.ebi.ac.uk/pdbsum/6g83 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6g83 ProSAT]</span></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">dprE1, MT3898 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=83331 MYCTO])</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> | | </table> |
| | == Function == | | == 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] | + | [https://www.uniprot.org/uniprot/DPRE1_MYCTU DPRE1_MYCTU] Involved in the epimerization of decaprenylphosphoryl ribose (DPR) to decaprenylphosphoryl arabinose (DPA) a precursor for arabinan synthesis in mycobacterial cell wall biosynthesis. Probably catalyzes the oxidation at C-2 of decaprenylphosphoryl ribose (DPR) to yield decaprenylphosphoryl 2-keto-ribose (DPX).<ref>PMID:16291675</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Decaprenylphospho-beta-D-ribofuranose 2-oxidase]] | + | [[Category: Large Structures]] |
| - | [[Category: Mycto]] | + | [[Category: Mycobacterium tuberculosis H37Rv]] |
| - | [[Category: Cole, S T]] | + | [[Category: Cole ST]] |
| - | [[Category: Makarov, V]] | + | [[Category: Makarov V]] |
| - | [[Category: Piton, J]] | + | [[Category: Piton J]] |
| - | [[Category: Btz]]
| + | |
| - | [[Category: Complex]]
| + | |
| - | [[Category: Dpre1]]
| + | |
| - | [[Category: Inhibitor]]
| + | |
| - | [[Category: M. tuberculosis]]
| + | |
| - | [[Category: Oxidoreductase]]
| + | |
| Structural highlights
Function
DPRE1_MYCTU Involved in the epimerization of decaprenylphosphoryl ribose (DPR) to decaprenylphosphoryl arabinose (DPA) a precursor for arabinan synthesis in mycobacterial cell wall biosynthesis. Probably catalyzes the oxidation at C-2 of decaprenylphosphoryl ribose (DPR) to yield decaprenylphosphoryl 2-keto-ribose (DPX).[1]
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[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Mikusova K, Huang H, Yagi T, Holsters M, Vereecke D, D'Haeze W, Scherman MS, Brennan PJ, McNeil MR, Crick DC. Decaprenylphosphoryl arabinofuranose, the donor of the D-arabinofuranosyl residues of mycobacterial arabinan, is formed via a two-step epimerization of decaprenylphosphoryl ribose. J Bacteriol. 2005 Dec;187(23):8020-5. PMID:16291675 doi:http://dx.doi.org/10.1128/JB.187.23.8020-8025.2005
- ↑ Piton J, Vocat A, Lupien A, Foo C, Riabova O, Makarov V, Cole ST. Structure-based drug design and characterization of sulfonyl-piperazine benzothiazinone inhibitors of DprE1 from Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2018 Jul 16. pii: AAC.00681-18. doi:, 10.1128/AAC.00681-18. PMID:30012754 doi:http://dx.doi.org/10.1128/AAC.00681-18
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