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| ==Structure of ICDH-1 from M.tuberculosis complexed with NADPH & Mn2+== | | ==Structure of ICDH-1 from M.tuberculosis complexed with NADPH & Mn2+== |
| <StructureSection load='4hcx' size='340' side='right' caption='[[4hcx]], [[Resolution|resolution]] 2.18Å' scene=''> | | <StructureSection load='4hcx' size='340' side='right'caption='[[4hcx]], [[Resolution|resolution]] 2.18Å' scene=''> |
| == Structural highlights == | | == Structural highlights == |
| <table><tr><td colspan='2'>[[4hcx]] is a 2 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=4HCX OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4HCX FirstGlance]. <br> | | <table><tr><td colspan='2'>[[4hcx]] is a 2 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=4HCX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4HCX FirstGlance]. <br> |
| </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene></td></tr> | | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.18Å</td></tr> |
| <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">icd, Rv3339c, MT3442, MTV016.39c ([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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene></td></tr> |
| <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Isocitrate_dehydrogenase_(NADP(+)) Isocitrate dehydrogenase (NADP(+))], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.1.42 1.1.1.42] </span></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=4hcx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4hcx OCA], [https://pdbe.org/4hcx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4hcx RCSB], [https://www.ebi.ac.uk/pdbsum/4hcx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4hcx ProSAT]</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=4hcx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4hcx OCA], [http://pdbe.org/4hcx PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4hcx RCSB], [http://www.ebi.ac.uk/pdbsum/4hcx PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4hcx ProSAT]</span></td></tr> | |
| </table> | | </table> |
| <div style="background-color:#fffaf0;">
| | == Function == |
| == Publication Abstract from PubMed == | | [https://www.uniprot.org/uniprot/IDH_MYCTU IDH_MYCTU] |
| Mycobacterium tuberculosis (Mtb) is the leading cause of death due to a bacterial infection. The success of the Mtb pathogen has largely been attributed to the nonreplicating, persistence phase of the life cycle, for which the glyoxylate shunt is required. In Escherichia coli flux through the shunt is controlled by regulation of isocitrate dehydrogenase (ICDH). In Mtb, the mechanism of regulation is unknown, and currently there is no mechanistic or structural information on ICDH. We optimized expression and purification to a yield high enough to perform the first detailed kinetic and structural studies for Mtb ICDH-1. A large solvent kinetic isotope effect (D2OV = 3.0 +/- 0.2, D2O[V/Kisocitrate] = 1.5 +/- 0.3) and a smaller primary kinetic isotope effect (DV = 1.3 +/- 0.1, D[V/K[2R-2H]isocitrate] = 1.5 +/- 0.2) allowed us to perform the first multiple kinetic isotope effect studies on any ICDH and suggest a chemical mechanism. In this mechanism, protonation of the enolate to form product alpha-ketoglutarate is the rate-limiting step. We report the first structure of Mtb ICDH-1 to 2.18 A by X-ray crystallography with NADPH and Mn2+ bound. It is a homodimer in which each subunit has a Rossmann fold, and a common top domain of interlocking beta sheets. Mtb ICDH-1 is most structurally similar to the R132H mutant human ICDH found in glioblastomas. Similar to human R132H ICDH, Mtb ICDH-1 also catalyses the formation of alpha-hydroxyglutarate. Our data suggest that regulation of Mtb ICDH-1 is novel.
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| Structure, Kinetic, and Chemical Mechanism of Isocitrate Dehydrogenase-1 from Mycobacterium tuberculosis.,Quartararo CE, Hazra S, Hadi T, Blanchard JS Biochemistry. 2013 Feb 14. PMID:23409873<ref>PMID:23409873</ref>
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| From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
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| </div>
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| <div class="pdbe-citations 4hcx" style="background-color:#fffaf0;"></div>
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| ==See Also== | | ==See Also== |
| *[[Isocitrate dehydrogenase|Isocitrate dehydrogenase]] | | *[[Isocitrate dehydrogenase 3D structures|Isocitrate dehydrogenase 3D structures]] |
| == References ==
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| <references/>
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| __TOC__ | | __TOC__ |
| </StructureSection> | | </StructureSection> |
| [[Category: Blanchard, J]] | | [[Category: Large Structures]] |
| [[Category: Hazra, S]] | | [[Category: Mycobacterium tuberculosis]] |
| [[Category: Dehydrogenase]] | | [[Category: Blanchard J]] |
| [[Category: Icdh-1]] | | [[Category: Hazra S]] |
| [[Category: Nadp binding]]
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| [[Category: Oxidoreductase]]
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| [[Category: Rossmann fold]]
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