6vb9
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==Covalent adduct of cis-2,3-epoxysuccinic acid with Isocitrate Lyase-1 from Mycobacterium tuberculosis== | ==Covalent adduct of cis-2,3-epoxysuccinic acid with Isocitrate Lyase-1 from Mycobacterium tuberculosis== | ||
| - | <StructureSection load='6vb9' size='340' side='right'caption='[[6vb9]]' scene=''> | + | <StructureSection load='6vb9' size='340' side='right'caption='[[6vb9]], [[Resolution|resolution]] 1.88Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6VB9 OCA]. For a <b>guided tour on the structure components</b> use [ | + | <table><tr><td colspan='2'>[[6vb9]] is a 4 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=6VB9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6VB9 FirstGlance]. <br> |
| - | </td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.881Å</td></tr> |
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACY:ACETIC+ACID'>ACY</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=OXD:OXALIC+ACID'>OXD</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=QVA:(2S,3R)-2-{[(2R)-2-amino-2-carboxyethyl]sulfanyl}-3-hydroxybutanedioic+acid'>QVA</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=6vb9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6vb9 OCA], [https://pdbe.org/6vb9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6vb9 RCSB], [https://www.ebi.ac.uk/pdbsum/6vb9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6vb9 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/ACEA_MYCTU ACEA_MYCTU] Catalyzes the formation of succinate and glyoxylate from isocitrate, a key step of the glyoxylate cycle. May be involved in the assimilation of one-carbon compounds via the isocitrate lyase-positive serine pathway (By similarity). | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | The isocitrate lyases (ICL1/2) are essential enzymes of Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis. At present, no ICL1/2 inhibitors have progressed to clinical evaluation, despite extensive drug discovery efforts. Herein, we surveyed succinate analogs against ICL1 and found that dicarboxylic acids constrained in their synperiplanar conformations, such as maleic acid, comprise uncompetitive inhibitors of ICL1 and inhibit more potently than their trans-isomers. From this, we identified cis-2,3 epoxysuccinic acid (cis-EpS) as a selective, irreversible covalent inactivator of Mtb ICL1 (kinact/Kinact= (5.0 +/- 1.4) x 10(4) M(-1) s(-1); Kinact = 200 +/- 50 nM), the most potent inactivator of ICL1 yet characterized. Crystallographic and mass spectrometric analysis demonstrated that Cys191 of ICL1 was S-malylated by cis-EpS, and a crystallographic "snapshot" of inactivation lent insight into the chemical mechanism of this inactivation. Proteomic analysis of E. coli lysates showed that cis-EpS selectively labeled plasmid-expressed Mtb ICL1. Consistently, cis-EpS, but not its trans-isomer, inhibited the growth of Mtb under conditions in which ICL function is essential. These findings encourage the development of analogs of cis-2,3-epoxysuccinate as antituberculosis agents. | ||
| + | |||
| + | Covalent Inactivation of Mycobacterium tuberculosis Isocitrate Lyase by cis-2,3-Epoxy-Succinic Acid.,Pham TV, Mellott DM, Moghadamchargari Z, Chen K, Krieger I, Laganowsky A, Sacchettini JC, Meek TD ACS Chem Biol. 2021 Mar 19;16(3):463-470. doi: 10.1021/acschembio.0c00740. Epub, 2021 Mar 10. PMID:33688722<ref>PMID:33688722</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 6vb9" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
| + | [[Category: Mycobacterium tuberculosis]] | ||
[[Category: Krieger IV]] | [[Category: Krieger IV]] | ||
[[Category: Meek TD]] | [[Category: Meek TD]] | ||
[[Category: Pham TV]] | [[Category: Pham TV]] | ||
[[Category: Sacchettini JC]] | [[Category: Sacchettini JC]] | ||
Current revision
Covalent adduct of cis-2,3-epoxysuccinic acid with Isocitrate Lyase-1 from Mycobacterium tuberculosis
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