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2cig
From Proteopedia
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| - | [[Image:2cig.gif|left|200px]]<br /> | ||
| - | <applet load="2cig" size="450" color="white" frame="true" align="right" spinBox="true" | ||
| - | caption="2cig, resolution 1.90Å" /> | ||
| - | '''DIHYDROFOLATE REDUCTASE FROM MYCOBACTERIUM TUBERCULOSIS INHIBITED BY THE ACYCLIC 4R ISOMER OF INH-NADP A DERIVATIVE OF THE PRODRUG ISONIAZID.'''<br /> | ||
| - | == | + | ==Dihydrofolate reductase from Mycobacterium tuberculosis inhibited by the acyclic 4R isomer of INH-NADP a derivative of the prodrug isoniazid.== |
| - | Isoniazid is a key drug used in the treatment of tuberculosis. Isoniazid | + | <StructureSection load='2cig' size='340' side='right'caption='[[2cig]], [[Resolution|resolution]] 1.90Å' scene=''> |
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[2cig]] 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=2CIG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2CIG FirstGlance]. <br> | ||
| + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.9Å</td></tr> | ||
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1DG:(4R)-ISONICOTINIC-ACETYL-NICOTINAMIDE-ADENINE+DINUCLEOTIDE'>1DG</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=2cig FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2cig OCA], [https://pdbe.org/2cig PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2cig RCSB], [https://www.ebi.ac.uk/pdbsum/2cig PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2cig ProSAT], [https://www.topsan.org/Proteins/TBSGC/2cig TOPSAN]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/DYR_MYCTU DYR_MYCTU] Key enzyme in folate metabolism. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis. | ||
| + | == Evolutionary Conservation == | ||
| + | [[Image:Consurf_key_small.gif|200px|right]] | ||
| + | Check<jmol> | ||
| + | <jmolCheckbox> | ||
| + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ci/2cig_consurf.spt"</scriptWhenChecked> | ||
| + | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | ||
| + | <text>to colour the structure by Evolutionary Conservation</text> | ||
| + | </jmolCheckbox> | ||
| + | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2cig ConSurf]. | ||
| + | <div style="clear:both"></div> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Isoniazid is a key drug used in the treatment of tuberculosis. Isoniazid is a pro-drug, which, after activation by the katG-encoded catalase peroxidase, reacts nonenzymatically with NAD(+) and NADP(+) to generate several isonicotinoyl adducts of these pyridine nucleotides. One of these, the acyclic 4S isomer of isoniazid-NAD, targets the inhA-encoded enoyl-ACP reductase, an enzyme essential for mycolic acid biosynthesis in Mycobacterium tuberculosis. Here we show that the acyclic 4R isomer of isoniazid-NADP inhibits the M. tuberculosis dihydrofolate reductase (DHFR), an enzyme essential for nucleic acid synthesis. This biologically relevant form of the isoniazid adduct is a subnanomolar bisubstrate inhibitor of M. tuberculosis DHFR. Expression of M. tuberculosis DHFR in Mycobacterium smegmatis mc(2)155 protects cells against growth inhibition by isoniazid by sequestering the drug. Thus, M. tuberculosis DHFR is the first new target for isoniazid identified in the last decade. | ||
| - | + | Mycobacterium tuberculosis dihydrofolate reductase is a target for isoniazid.,Argyrou A, Vetting MW, Aladegbami B, Blanchard JS Nat Struct Mol Biol. 2006 May;13(5):408-13. Epub 2006 Apr 30. PMID:16648861<ref>PMID:16648861</ref> | |
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| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | + | </div> | |
| - | + | <div class="pdbe-citations 2cig" style="background-color:#fffaf0;"></div> | |
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| - | + | ==See Also== | |
| + | *[[Dihydrofolate reductase 3D structures|Dihydrofolate reductase 3D structures]] | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Mycobacterium tuberculosis H37Rv]] | ||
| + | [[Category: Aladegbami B]] | ||
| + | [[Category: Argyrou A]] | ||
| + | [[Category: Blanchard JS]] | ||
| + | [[Category: Vetting MW]] | ||
Current revision
Dihydrofolate reductase from Mycobacterium tuberculosis inhibited by the acyclic 4R isomer of INH-NADP a derivative of the prodrug isoniazid.
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