6de5
From Proteopedia
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==Mycobacterium tuberculosis Rv2671 complexed with beta-NADPH and 6-ethyl-5-{(3S)-3-[2-methoxy-5-(pyridin-4-yl)phenyl]but-1-yn-1-yl}pyrimidine-2,4-diamine== | ==Mycobacterium tuberculosis Rv2671 complexed with beta-NADPH and 6-ethyl-5-{(3S)-3-[2-methoxy-5-(pyridin-4-yl)phenyl]but-1-yn-1-yl}pyrimidine-2,4-diamine== | ||
| - | <StructureSection load='6de5' size='340' side='right' caption='[[6de5]], [[Resolution|resolution]] 2.30Å' scene=''> | + | <StructureSection load='6de5' size='340' side='right'caption='[[6de5]], [[Resolution|resolution]] 2.30Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>[[6de5]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6DE5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6DE5 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6de5]] is a 1 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=6DE5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6DE5 FirstGlance]. <br> |
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=G8J:6-ethyl-5-{(3S)-3-[2-methoxy-5-(pyridin-4-yl)phenyl]but-1-yn-1-yl}pyrimidine-2,4-diamine'>G8J</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=G8J:6-ethyl-5-{(3S)-3-[2-methoxy-5-(pyridin-4-yl)phenyl]but-1-yn-1-yl}pyrimidine-2,4-diamine'>G8J</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene></td></tr> | ||
| + | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ribD, Rv2671 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=83332 MYCTU])</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=6de5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6de5 OCA], [http://pdbe.org/6de5 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6de5 RCSB], [http://www.ebi.ac.uk/pdbsum/6de5 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6de5 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=6de5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6de5 OCA], [http://pdbe.org/6de5 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6de5 RCSB], [http://www.ebi.ac.uk/pdbsum/6de5 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6de5 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| + | <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. | ||
| + | |||
| + | 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> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 6de5" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| + | [[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 Rv2671 complexed with beta-NADPH and 6-ethyl-5-{(3S)-3-[2-methoxy-5-(pyridin-4-yl)phenyl]but-1-yn-1-yl}pyrimidine-2,4-diamine
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