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4m3b

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==Rapid and efficient design of new inhibitors of Mycobacterium tuberculosis transcriptional repressor EthR using fragment growing, merging and linking approaches==
==Rapid and efficient design of new inhibitors of Mycobacterium tuberculosis transcriptional repressor EthR using fragment growing, merging and linking approaches==
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<StructureSection load='4m3b' size='340' side='right' caption='[[4m3b]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
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<StructureSection load='4m3b' size='340' side='right'caption='[[4m3b]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[4m3b]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4M3B OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4M3B FirstGlance]. <br>
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<table><tr><td colspan='2'>[[4m3b]] is a 1 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=4M3B OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4M3B 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=2B2:4-(2-METHYL-1,3-THIAZOL-4-YL)-N-(3,3,3-TRIFLUOROPROPYL)BENZAMIDE'>2B2</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.001&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4m3d|4m3d]], [[4m3e|4m3e]], [[4m3f|4m3f]], [[4m3g|4m3g]]</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2B2:4-(2-METHYL-1,3-THIAZOL-4-YL)-N-(3,3,3-TRIFLUOROPROPYL)BENZAMIDE'>2B2</scene></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=4m3b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4m3b OCA], [http://pdbe.org/4m3b PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4m3b RCSB], [http://www.ebi.ac.uk/pdbsum/4m3b PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4m3b ProSAT]</span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4m3b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4m3b OCA], [https://pdbe.org/4m3b PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4m3b RCSB], [https://www.ebi.ac.uk/pdbsum/4m3b PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4m3b ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
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[[http://www.uniprot.org/uniprot/ETHR_MYCTU ETHR_MYCTU]] Involved in the repression of the monooxygenase EthA which is responsible of the formation of the active metabolite of ethionamide (ETH).<ref>PMID:10869356</ref> <ref>PMID:10944230</ref>
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[https://www.uniprot.org/uniprot/ETHR_MYCTU ETHR_MYCTU] Involved in the repression of the monooxygenase EthA which is responsible of the formation of the active metabolite of ethionamide (ETH).<ref>PMID:10869356</ref> <ref>PMID:10944230</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Tuberculosis remains a major cause of mortality and morbidity, killing each year more than one million people. Although the combined use of first line antibiotics (isoniazid, rifampicin, pyrazinamide, and ethambutol) is efficient to treat most patients, the rapid emergence of multidrug resistant strains of Mycobacterium tuberculosis stresses the need for alternative therapies. Mycobacterial transcriptional repressor EthR is a key player in the control of second-line drugs bioactivation such as ethionamide and has been shown to impair the sensitivity of the human pathogen Mycobacterium tuberculosis to this antibiotic. As a way to identify new potent ligands of this protein, we have developed fragment-based approaches. In the current study, we combined surface plasmon resonance assay, X-ray crystallography, and ligand efficiency driven design for the rapid discovery and optimization of new chemotypes of EthR ligands starting from a fragment. The design, synthesis, and in vitro and ex vivo activities of these compounds will be discussed.
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Ligand Efficiency Driven Design of New Inhibitors of Mycobacterium tuberculosis Transcriptional Repressor EthR Using Fragment Growing, Merging, and Linking Approaches.,Villemagne B, Flipo M, Blondiaux N, Crauste C, Malaquin S, Leroux F, Piveteau C, Villeret V, Brodin P, Villoutreix BO, Sperandio O, Soror SH, Wohlkonig A, Wintjens R, Deprez B, Baulard AR, Willand N J Med Chem. 2014 Jun 12;57(11):4876-88. doi: 10.1021/jm500422b. Epub 2014 May 28. PMID:24818704<ref>PMID:24818704</ref>
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==See Also==
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*[[Tetracycline repressor protein 3D structures|Tetracycline repressor protein 3D structures]]
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 4m3b" style="background-color:#fffaf0;"></div>
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== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Baulard, A]]
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[[Category: Large Structures]]
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[[Category: Blondiaux, N]]
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[[Category: Mycobacterium tuberculosis H37Rv]]
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[[Category: Brodin, P]]
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[[Category: Baulard A]]
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[[Category: Crauste, C]]
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[[Category: Blondiaux N]]
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[[Category: Deprez, B]]
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[[Category: Brodin P]]
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[[Category: Flipo, M]]
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[[Category: Crauste C]]
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[[Category: Leroux, F]]
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[[Category: Deprez B]]
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[[Category: Malaquin, S]]
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[[Category: Flipo M]]
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[[Category: Piveteau, C]]
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[[Category: Leroux F]]
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[[Category: Sperandio, O]]
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[[Category: Malaquin S]]
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[[Category: Villemagne, B]]
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[[Category: Piveteau C]]
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[[Category: Villeret, V]]
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[[Category: Sperandio O]]
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[[Category: Villoutreix, B]]
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[[Category: Villemagne B]]
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[[Category: Willand, N]]
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[[Category: Villeret V]]
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[[Category: Wintjens, R]]
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[[Category: Villoutreix B]]
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[[Category: Wohlkonig, A]]
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[[Category: Willand N]]
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[[Category: Helix-turn-helix dna binding protein]]
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[[Category: Wintjens R]]
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[[Category: Inhibitor]]
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[[Category: Wohlkonig A]]
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[[Category: Tetr-family]]
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[[Category: Transcription repressor-inhibitor complex]]
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[[Category: Transcriptional regulatory repressor]]
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Rapid and efficient design of new inhibitors of Mycobacterium tuberculosis transcriptional repressor EthR using fragment growing, merging and linking approaches

PDB ID 4m3b

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