View source for 6ddp


==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]] 1.49&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6ddp]] is a 4 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=6DDP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6DDP 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]] 1.49&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6ddp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ddp OCA], [https://pdbe.org/6ddp PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6ddp RCSB], [https://www.ebi.ac.uk/pdbsum/6ddp PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6ddp ProSAT]</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.
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== 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&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 6ddp" style="background-color:#fffaf0;"></div>

==See Also==
*[[Dihydrofolate reductase 3D structures|Dihydrofolate reductase 3D structures]]
== References ==
<references/>
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</StructureSection>
[[Category: Large Structures]]
[[Category: Mycobacterium tuberculosis H37Rv]]
[[Category: Hajian B]]
[[Category: Wright D]]