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3g1l

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Revision as of 11:50, 5 August 2016

EthR from Mycobacterium tuberculosis in complex with compound BDM14744

Structural highlights

3g1l is a 1 chain structure with sequence from "bacillus_tuberculosis"_(zopf_1883)_klein_1884 "bacillus tuberculosis" (zopf 1883) klein 1884. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Related:	1u9n, 1u9o, 3g1m, 3g1o
Gene:	ethR, MT3970, Rv3855 ("Bacillus tuberculosis" (Zopf 1883) Klein 1884)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[ETHR_MYCTU] Involved in the repression of the monooxygenase EthA which is responsible of the formation of the active metabolite of ethionamide (ETH).^[1] ^[2]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

The side effects associated with tuberculosis therapy bring with them the risk of noncompliance and subsequent drug resistance. Increasing the therapeutic index of antituberculosis drugs should thus improve treatment effectiveness. Several antituberculosis compounds require in situ metabolic activation to become inhibitory. Various thiocarbamide-containing drugs, including ethionamide, are activated by the mycobacterial monooxygenase EthA, the production of which is controlled by the transcriptional repressor EthR. Here we identify drug-like inhibitors of EthR that boost the bioactivation of ethionamide. Compounds designed and screened for their capacity to inhibit EthR-DNA interaction were co-crystallized with EthR. We exploited the three-dimensional structures of the complexes for the synthesis of improved analogs that boosted the ethionamide potency in culture more than tenfold. In Mycobacterium tuberculosis-infected mice, one of these analogs, BDM31343, enabled a substantially reduced dose of ethionamide to lessen the mycobacterial load as efficiently as the conventional higher-dose treatment. This provides proof of concept that inhibiting EthR improves the therapeutic index of thiocarbamide derivatives, which should prompt reconsideration of their use as first-line drugs.

Synthetic EthR inhibitors boost antituberculous activity of ethionamide.,Willand N, Dirie B, Carette X, Bifani P, Singhal A, Desroses M, Leroux F, Willery E, Mathys V, Deprez-Poulain R, Delcroix G, Frenois F, Aumercier M, Locht C, Villeret V, Deprez B, Baulard AR Nat Med. 2009 May;15(5):537-44. Epub 2009 May 3. PMID:19412174^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Baulard AR, Betts JC, Engohang-Ndong J, Quan S, McAdam RA, Brennan PJ, Locht C, Besra GS. Activation of the pro-drug ethionamide is regulated in mycobacteria. J Biol Chem. 2000 Sep 8;275(36):28326-31. PMID:10869356 doi:10.1074/jbc.M003744200
↑ DeBarber AE, Mdluli K, Bosman M, Bekker LG, Barry CE 3rd. Ethionamide activation and sensitivity in multidrug-resistant Mycobacterium tuberculosis. Proc Natl Acad Sci U S A. 2000 Aug 15;97(17):9677-82. PMID:10944230
↑ Willand N, Dirie B, Carette X, Bifani P, Singhal A, Desroses M, Leroux F, Willery E, Mathys V, Deprez-Poulain R, Delcroix G, Frenois F, Aumercier M, Locht C, Villeret V, Deprez B, Baulard AR. Synthetic EthR inhibitors boost antituberculous activity of ethionamide. Nat Med. 2009 May;15(5):537-44. Epub 2009 May 3. PMID:19412174 doi:10.1038/nm.1950

1 Structural highlights
2 Function
3 Evolutionary Conservation
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/3g1l"

@@ Line 1: / Line 1: @@
 ==EthR from Mycobacterium tuberculosis in complex with compound BDM14744==
 <StructureSection load='3g1l' size='340' side='right' caption='[[3g1l]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
@@ Line 6: / Line 7: @@
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1u9n|1u9n]], [[1u9o|1u9o]], [[3g1m|3g1m]], [[3g1o|3g1o]]</td></tr>
 <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ethR, MT3970, Rv3855 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1773 "Bacillus tuberculosis" (Zopf 1883) Klein 1884])</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=3g1l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3g1l OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3g1l RCSB], [http://www.ebi.ac.uk/pdbsum/3g1l PDBsum]</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=3g1l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3g1l OCA], [http://pdbe.org/3g1l PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3g1l RCSB], [http://www.ebi.ac.uk/pdbsum/3g1l PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3g1l ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 18: / Line 19: @@
     <text>to colour the structure by Evolutionary Conservation</text>
   </jmolCheckbox>
-</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf].
+</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=3g1l ConSurf].
 <div style="clear:both"></div>
 <div style="background-color:#fffaf0;">
@@ Line 28: / Line 29: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 3g1l" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>

3g1l

From Proteopedia

Revision as of 11:50, 5 August 2016

EthR from Mycobacterium tuberculosis in complex with compound BDM14744

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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