4ncr

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{{STRUCTURE_4ncr| PDB=4ncr | SCENE= }}
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==Crystal structure of M. tuberculosis DprE1 in complex with PBTZ169==
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===Crystal structure of M. tuberculosis DprE1 in complex with PBTZ169===
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<StructureSection load='4ncr' size='340' side='right' caption='[[4ncr]], [[Resolution|resolution]] 1.88&Aring;' scene=''>
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{{ABSTRACT_PUBMED_24500695}}
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== Structural highlights ==
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<table><tr><td colspan='2'>[[4ncr]] is a 2 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=4NCR OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4NCR FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=26J:2-(4-(CYCLOHEXYLMETHYL)PIPERAZIN-1-YL)-8-NITRO-6-(TRIFLUOROMETHYL)-4H-BENZO[E][1,3]THIAZIN-4-ONE,+BOUND+FORM'>26J</scene>, <scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=IMD:IMIDAZOLE'>IMD</scene></td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4fdp|4fdp]], [[4f4q|4f4q]]</td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">dprE1, MT3898, Rv3790 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=83332 MYCTU])</td></tr>
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<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=4ncr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ncr OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4ncr RCSB], [http://www.ebi.ac.uk/pdbsum/4ncr PDBsum]</span></td></tr>
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</table>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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The benzothiazinone lead compound, BTZ043, kills Mycobacterium tuberculosis by inhibiting the essential flavo-enzyme DprE1, decaprenylphosphoryl-beta-D-ribose 2-epimerase. Here, we synthesized a new series of piperazine-containing benzothiazinones (PBTZ) and show that, like BTZ043, the preclinical candidate PBTZ169 binds covalently to DprE1. The crystal structure of the DprE1-PBTZ169 complex reveals formation of a semimercaptal adduct with Cys387 in the active site and explains the irreversible inactivation of the enzyme. Compared to BTZ043, PBTZ169 has improved potency, safety and efficacy in zebrafish and mouse models of tuberculosis (TB). When combined with other TB drugs, PBTZ169 showed additive activity against M. tuberculosis in vitro except with bedaquiline (BDQ) where synergy was observed. A new regimen comprising PBTZ169, BDQ and pyrazinamide was found to be more efficacious than the standard three drug treatment in a murine model of chronic disease. PBTZ169 is thus an attractive drug candidate to treat TB in humans.
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==Function==
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Towards a new combination therapy for tuberculosis with next generation benzothiazinones.,Makarov V, Lechartier B, Zhang M, Neres J, van der Sar AM, Raadsen SA, Hartkoorn RC, Ryabova OB, Vocat A, Decosterd LA, Widmer N, Buclin T, Bitter W, Andries K, Pojer F, Dyson PJ, Cole ST EMBO Mol Med. 2014 Feb 5. PMID:24500695<ref>PMID:24500695</ref>
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[[http://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>
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==About this Structure==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[4ncr]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4NCR OCA].
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</div>
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== References ==
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==Reference==
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<references/>
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<ref group="xtra">PMID:024500695</ref><references group="xtra"/><references/>
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__TOC__
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[[Category: Cole, S T.]]
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</StructureSection>
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[[Category: Neres, J.]]
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[[Category: Myctu]]
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[[Category: Pojer, F.]]
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[[Category: Cole, S T]]
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[[Category: Neres, J]]
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[[Category: Pojer, F]]
[[Category: Decaprenylphosphoryl-beta-d-ribose oxidase]]
[[Category: Decaprenylphosphoryl-beta-d-ribose oxidase]]
[[Category: Oxidoreductase-oxidoreductase inhibitor complex]]
[[Category: Oxidoreductase-oxidoreductase inhibitor complex]]

Revision as of 18:49, 21 December 2014

Crystal structure of M. tuberculosis DprE1 in complex with PBTZ169

4ncr, resolution 1.88Å

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