5oel

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'''Unreleased structure'''
 
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The entry 5oel is ON HOLD until Paper Publication
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==Mycobacterium tuberculosis DprE1 mutant Y314C in complex with TCA1==
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<StructureSection load='5oel' size='340' side='right' caption='[[5oel]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[5oel]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5OEL OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5OEL 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=1W6:ETHYL+({2-[(1,3-BENZOTHIAZOL-2-YLCARBONYL)AMINO]THIOPHEN-3-YL}CARBONYL)CARBAMATE'>1W6</scene>, <scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene></td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4kw5|4kw5]]</td></tr>
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<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>
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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=5oel FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5oel OCA], [http://pdbe.org/5oel PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5oel RCSB], [http://www.ebi.ac.uk/pdbsum/5oel PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5oel ProSAT]</span></td></tr>
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</table>
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== Function ==
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[[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]
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Mycobacterium tuberculosis (Mtb) DprE1, an essential isomerase for the biosynthesis of the mycobacterial cell wall, is a validated target for tuberculosis (TB) drug development. Here we report the X-ray crystal structures of DprE1 and the DprE1 resistant mutant (Y314C) in complexes with TCA1 derivatives to elucidate the molecular basis of their inhibitory activities and an unconventional resistance mechanism, which enabled us to optimize the potency of the analogs. The selected lead compound showed excellent in vitro and in vivo activities, and low risk of toxicity profile except for the inhibition of CYP2C9. A crystal structure of CYP2C9 in complex with a TCA1 analog revealed the similar interaction patterns to the DprE1-TCA1 complex. Guided by the structures, an optimized molecule was generated with differential inhibitory activities against DprE1 and CYP2C9, which provides insights for development of a clinical candidate to treat TB.
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Authors: Futterer, K., Batt, S.M., Besra, G.S.
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Determinants of the Inhibition of DprE1 and CYP2C9 by Antitubercular Thiophenes.,Liu R, Lyu X, Batt SM, Hsu MH, Harbut MB, Vilcheze C, Cheng B, Ajayi K, Yang B, Yang Y, Guo H, Lin C, Gan F, Wang C, Franzblau SG, Jacobs WR Jr, Besra GS, Johnson EF, Petrassi M, Chatterjee AK, Futterer K, Wang F Angew Chem Int Ed Engl. 2017 Aug 16. doi: 10.1002/anie.201707324. PMID:28815830<ref>PMID:28815830</ref>
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Description: Mycobacterium tuberculosis DprE1 mutant Y314C in complex with TCA1
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[Category: Unreleased Structures]]
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</div>
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[[Category: Besra, G.S]]
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<div class="pdbe-citations 5oel" style="background-color:#fffaf0;"></div>
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[[Category: Batt, S.M]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
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[[Category: Decaprenylphospho-beta-D-ribofuranose 2-oxidase]]
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[[Category: Batt, S M]]
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[[Category: Besra, G S]]
[[Category: Futterer, K]]
[[Category: Futterer, K]]
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[[Category: Fad-containing oxidoreductase decaprenylphosphoarabinose synthesis]]
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[[Category: Oxidoreductase]]

Revision as of 05:23, 16 May 2018

Mycobacterium tuberculosis DprE1 mutant Y314C in complex with TCA1

5oel, resolution 2.20Å

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