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==Crystal Structure of the Catalytic Domain of the Inosine Monophosphate Dehydrogenase from Mycobacterium tuberculosis in the complex with XMP and NAD== | ==Crystal Structure of the Catalytic Domain of the Inosine Monophosphate Dehydrogenase from Mycobacterium tuberculosis in the complex with XMP and NAD== | ||
<StructureSection load='4zqm' size='340' side='right' caption='[[4zqm]], [[Resolution|resolution]] 1.60Å' scene=''> | <StructureSection load='4zqm' size='340' side='right' caption='[[4zqm]], [[Resolution|resolution]] 1.60Å' scene=''> | ||
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=NAD:NICOTINAMIDE-ADENINE-DINUCLEOTIDE'>NAD</scene>, <scene name='pdbligand=XMP:XANTHOSINE-5-MONOPHOSPHATE'>XMP</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=NAD:NICOTINAMIDE-ADENINE-DINUCLEOTIDE'>NAD</scene>, <scene name='pdbligand=XMP:XANTHOSINE-5-MONOPHOSPHATE'>XMP</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4zqn|4zqn]], [[4zqo|4zqo]], [[4zqp|4zqp]], [[4zqr|4zqr]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4zqn|4zqn]], [[4zqo|4zqo]], [[4zqp|4zqp]], [[4zqr|4zqr]]</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=4zqm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zqm OCA], [http://pdbe.org/4zqm PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4zqm RCSB], [http://www.ebi.ac.uk/pdbsum/4zqm 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=4zqm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zqm OCA], [http://pdbe.org/4zqm PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4zqm RCSB], [http://www.ebi.ac.uk/pdbsum/4zqm PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4zqm ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
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__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Anderson, W F]] | ||
[[Category: Structural genomic]] | [[Category: Structural genomic]] | ||
[[Category: Gu, M]] | [[Category: Gu, M]] | ||
Revision as of 11:04, 9 March 2017
Crystal Structure of the Catalytic Domain of the Inosine Monophosphate Dehydrogenase from Mycobacterium tuberculosis in the complex with XMP and NADCrystal Structure of the Catalytic Domain of the Inosine Monophosphate Dehydrogenase from Mycobacterium tuberculosis in the complex with XMP and NAD
Structural highlights
Function[IMDH_MYCTU] Catalyzes the conversion of inosine 5'-phosphate (IMP) to xanthosine 5'-phosphate (XMP), the first committed and rate-limiting step in the de novo synthesis of guanine nucleotides, and therefore plays an important role in the regulation of cell growth.[HAMAP-Rule:MF_01964] Publication Abstract from PubMedTuberculosis (TB) remains a worldwide problem and the need for new drugs is increasingly more urgent with the emergence of multidrug- and extensively-drug resistant TB. Inosine 5'-monophosphate dehydrogenase 2 (IMPDH2) from Mycobacterium tuberculosis (Mtb) is an attractive drug target. The enzyme catalyzes the conversion of inosine 5'-monophosphate into xanthosine 5'-monophosphate with the concomitant reduction of NAD+ to NADH. This reaction controls flux into the guanine nucleotide pool. We report seventeen selective IMPDH inhibitors with antitubercular activity. The crystal structures of a deletion mutant of MtbIMPDH2 in the apo form and in complex with the product XMP and substrate NAD+ are determined. We also report the structures of complexes with IMP and three structurally distinct inhibitors, including two with antitubercular activity. These structures will greatly facilitate the development of MtbIMPDH2-targeted antibiotics. Mycobacterium tuberculosis IMPDH in Complexes with Substrates, Products and Antitubercular Compounds.,Makowska-Grzyska M, Kim Y, Gorla SK, Wei Y, Mandapati K, Zhang M, Maltseva N, Modi G, Boshoff HI, Gu M, Aldrich C, Cuny GD, Hedstrom L, Joachimiak A PLoS One. 2015 Oct 6;10(10):e0138976. doi: 10.1371/journal.pone.0138976., eCollection 2015. PMID:26440283[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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