6ddp
From Proteopedia
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==Mycobacterium tuberculosis Dihydrofolate Reductase complexed with beta-NADPH and 3'-[(2R)-4-(2,4-diamino-6-ethylpyrimidin-5-yl)but-3-yn-2-yl]-5'-methoxy[1,1'-biphenyl]-4-carboxylic acid== | ==Mycobacterium tuberculosis Dihydrofolate Reductase complexed with beta-NADPH and 3'-[(2R)-4-(2,4-diamino-6-ethylpyrimidin-5-yl)but-3-yn-2-yl]-5'-methoxy[1,1'-biphenyl]-4-carboxylic acid== | ||
| - | <StructureSection load='6ddp' size='340' side='right' caption='[[6ddp]], [[Resolution|resolution]] 1.49Å' scene=''> | + | <StructureSection load='6ddp' size='340' side='right'caption='[[6ddp]], [[Resolution|resolution]] 1.49Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>[[6ddp]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6DDP OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6DDP FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6ddp]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Myctu Myctu]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6DDP OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6DDP FirstGlance]. <br> |
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=G6Y:3-[(2R)-4-(2,4-diamino-6-ethylpyrimidin-5-yl)but-3-yn-2-yl]-5-methoxy[1,1-biphenyl]-4-carboxylic+acid'>G6Y</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=G6Y:3-[(2R)-4-(2,4-diamino-6-ethylpyrimidin-5-yl)but-3-yn-2-yl]-5-methoxy[1,1-biphenyl]-4-carboxylic+acid'>G6Y</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5ja3|5ja3]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5ja3|5ja3]]</td></tr> | ||
| + | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">folA, dfrA, Rv2763c, MTV002.28c ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=83332 MYCTU])</td></tr> | ||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Dihydrofolate_reductase Dihydrofolate reductase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.5.1.3 1.5.1.3] </span></td></tr> | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Dihydrofolate_reductase Dihydrofolate reductase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.5.1.3 1.5.1.3] </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=6ddp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ddp OCA], [http://pdbe.org/6ddp PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ddp RCSB], [http://www.ebi.ac.uk/pdbsum/6ddp PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ddp 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=6ddp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ddp OCA], [http://pdbe.org/6ddp PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ddp RCSB], [http://www.ebi.ac.uk/pdbsum/6ddp PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ddp ProSAT]</span></td></tr> | ||
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== Function == | == Function == | ||
[[http://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. | [[http://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. | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | The folate biosynthetic pathway offers many druggable targets that have yet to be exploited in tuberculosis therapy. Herein, we have identified a series of small molecules that interrupt Mycobacterium tuberculosis (Mtb) folate metabolism by dual targeting of dihydrofolate reductase (DHFR), a key enzyme in the folate pathway, and its functional analog, Rv2671. We have also compared the antifolate activity of these compounds with that of para-aminosalicylic acid (PAS). We found that the bioactive metabolite of PAS, in addition to previously reported activity against DHFR, inhibits flavin-dependent thymidylate synthase in Mtb, suggesting a multi-targeted mechanism of action for this drug. Finally, we have shown that antifolate treatment in Mtb decreases the production of mycolic acids, most likely due to perturbation of the activated methyl cycle. We conclude that multi-targeting of the folate pathway in Mtb is associated with highly potent anti-mycobacterial activity. | ||
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| + | Drugging the Folate Pathway in Mycobacterium tuberculosis: The Role of Multi-targeting Agents.,Hajian B, Scocchera E, Shoen C, Krucinska J, Viswanathan K, G-Dayanandan N, Erlandsen H, Estrada A, Mikusova K, Kordulakova J, Cynamon M, Wright D Cell Chem Biol. 2019 Jun 20;26(6):781-791.e6. doi:, 10.1016/j.chembiol.2019.02.013. Epub 2019 Mar 28. PMID:30930162<ref>PMID:30930162</ref> | ||
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| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 6ddp" style="background-color:#fffaf0;"></div> | ||
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| + | ==See Also== | ||
| + | *[[Dihydrofolate reductase 3D structures|Dihydrofolate reductase 3D structures]] | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Dihydrofolate reductase]] | [[Category: Dihydrofolate reductase]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Myctu]] | ||
[[Category: Hajian, B]] | [[Category: Hajian, B]] | ||
[[Category: Wright, D]] | [[Category: Wright, D]] | ||
Revision as of 06:17, 10 July 2019
Mycobacterium tuberculosis Dihydrofolate Reductase complexed with beta-NADPH and 3'-[(2R)-4-(2,4-diamino-6-ethylpyrimidin-5-yl)but-3-yn-2-yl]-5'-methoxy[1,1'-biphenyl]-4-carboxylic acid
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