View source for 5oel


==Mycobacterium tuberculosis DprE1 mutant Y314C in complex with TCA1==
<StructureSection load='5oel' size='340' side='right'caption='[[5oel]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5oel]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis_CDC1551 Mycobacterium tuberculosis CDC1551]. 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 [https://proteopedia.org/fgij/fg.htm?mol=5OEL FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.2&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5oel FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5oel OCA], [https://pdbe.org/5oel PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5oel RCSB], [https://www.ebi.ac.uk/pdbsum/5oel PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5oel ProSAT]</span></td></tr>
</table>
== Function ==
[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> 
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== Publication Abstract from PubMed ==
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.

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>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 5oel" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Large Structures]]
[[Category: Mycobacterium tuberculosis CDC1551]]
[[Category: Batt SM]]
[[Category: Besra GS]]
[[Category: Futterer K]]