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3s9i

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==Crystal structure of Mycobacterium tuberculosis malate synthase in complex with 2-4-dioxo-4-phenylbutanoic acid inhibitor==
==Crystal structure of Mycobacterium tuberculosis malate synthase in complex with 2-4-dioxo-4-phenylbutanoic acid inhibitor==
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<StructureSection load='3s9i' size='340' side='right' caption='[[3s9i]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
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<StructureSection load='3s9i' size='340' side='right'caption='[[3s9i]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[3s9i]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/"bacillus_tuberculosis"_(zopf_1883)_klein_1884 "bacillus tuberculosis" (zopf 1883) klein 1884]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3S9I OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3S9I FirstGlance]. <br>
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<table><tr><td colspan='2'>[[3s9i]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3S9I OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3S9I 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=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=XI7:2-4-DIOXO-4-PHENYLBUTANOIC+ACID'>XI7</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]] 1.9&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1n8i|1n8i]], [[1n8w|1n8w]], [[2gq3|2gq3]], [[3s9z|3s9z]], [[3sad|3sad]], [[3saz|3saz]], [[3sb0|3sb0]]</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=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=XI7:2-4-DIOXO-4-PHENYLBUTANOIC+ACID'>XI7</scene></td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">glcB, MT1885, MTCY1A11.06, Rv1837c ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1773 "Bacillus tuberculosis" (Zopf 1883) Klein 1884])</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=3s9i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3s9i OCA], [https://pdbe.org/3s9i PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3s9i RCSB], [https://www.ebi.ac.uk/pdbsum/3s9i PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3s9i ProSAT]</span></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/Malate_synthase Malate synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.3.3.9 2.3.3.9] </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=3s9i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3s9i OCA], [http://pdbe.org/3s9i PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3s9i RCSB], [http://www.ebi.ac.uk/pdbsum/3s9i PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3s9i ProSAT]</span></td></tr>
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</table>
</table>
== Function ==
== Function ==
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[[http://www.uniprot.org/uniprot/MASZ_MYCTU MASZ_MYCTU]] Involved in the glycolate utilization. Catalyzes the condensation and subsequent hydrolysis of acetyl-coenzyme A (acetyl-CoA) and glyoxylate to form malate and CoA (By similarity).[HAMAP-Rule:MF_00641]
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[https://www.uniprot.org/uniprot/MASZ_MYCTU MASZ_MYCTU] Involved in the glycolate utilization. Catalyzes the condensation and subsequent hydrolysis of acetyl-coenzyme A (acetyl-CoA) and glyoxylate to form malate and CoA (By similarity).[HAMAP-Rule:MF_00641]
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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The glyoxylate shunt plays an important role in fatty acid metabolism and has been shown to be critical to survival of several pathogens involved in chronic infections. For Mycobacterium tuberculosis (Mtb), a strain with a defective glyoxylate shunt was previously shown to be unable to establish infection in a mouse model. We report the development of phenyl-diketo acid (PDKA) inhibitors of malate synthase (GlcB), one of two glyoxylate shunt enzymes, using structure-based methods. PDKA inhibitors were active against Mtb grown on acetate, and overexpression of GlcB ameliorated this inhibition. Crystal structures of complexes of GlcB with PDKA inhibitors guided optimization of potency. A selected PDKA compound demonstrated efficacy in a mouse model of tuberculosis. The discovery of these PDKA derivatives provides chemical validation of GlcB as an attractive target for tuberculosis therapeutics.
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Structure-guided discovery of phenyl-diketo acids as potent inhibitors of M. tuberculosis malate synthase.,Krieger IV, Freundlich JS, Gawandi VB, Roberts JP, Gawandi VB, Sun Q, Owen JL, Fraile MT, Huss SI, Lavandera JL, Ioerger TR, Sacchettini JC Chem Biol. 2012 Dec 21;19(12):1556-67. doi: 10.1016/j.chembiol.2012.09.018. PMID:23261599<ref>PMID:23261599</ref>
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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 3s9i" style="background-color:#fffaf0;"></div>
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==See Also==
==See Also==
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*[[Malate synthase|Malate synthase]]
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*[[Malate synthase 3D structures|Malate synthase 3D structures]]
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== References ==
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<references/>
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Malate synthase]]
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[[Category: Large Structures]]
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[[Category: Krieger, I V]]
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[[Category: Mycobacterium tuberculosis]]
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[[Category: Sacchettini, J C]]
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[[Category: Krieger IV]]
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[[Category: Sun, Q]]
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[[Category: Sacchettini JC]]
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[[Category: XMTB, Mycobacterium Tuberculosis Structural Proteomics Project]]
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[[Category: Sun Q]]
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[[Category: Inhibitor complex]]
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[[Category: Mycobacterium tuberculosis structural proteomics project]]
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[[Category: Structural genomic]]
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[[Category: Transferase-transferase inhibitor complex]]
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[[Category: Xmtb]]
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Current revision

Crystal structure of Mycobacterium tuberculosis malate synthase in complex with 2-4-dioxo-4-phenylbutanoic acid inhibitor

PDB ID 3s9i

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