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7ctz
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==Wild-type plasmodium falciparum dihydrofolate reductase-thymidylate synthase (PfDHFR-TS) complexed with fragment 148, NADPH, and dUMP== | ==Wild-type plasmodium falciparum dihydrofolate reductase-thymidylate synthase (PfDHFR-TS) complexed with fragment 148, NADPH, and dUMP== | ||
| - | <StructureSection load='7ctz' size='340' side='right'caption='[[7ctz]]' scene=''> | + | <StructureSection load='7ctz' size='340' side='right'caption='[[7ctz]], [[Resolution|resolution]] 2.65Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7CTZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7CTZ FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[7ctz]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Plasmodium_falciparum Plasmodium falciparum]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7CTZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7CTZ FirstGlance]. <br> |
| - | </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=7ctz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ctz OCA], [https://pdbe.org/7ctz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ctz RCSB], [https://www.ebi.ac.uk/pdbsum/7ctz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ctz ProSAT]</span></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.65Å</td></tr> |
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GF6:1-[3-(trifluoromethyl)phenyl]urea'>GF6</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene>, <scene name='pdbligand=UMP:2-DEOXYURIDINE+5-MONOPHOSPHATE'>UMP</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=7ctz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ctz OCA], [https://pdbe.org/7ctz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ctz RCSB], [https://www.ebi.ac.uk/pdbsum/7ctz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ctz ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/Q8I1R6_PLAF7 Q8I1R6_PLAF7] Bifunctional enzyme. Involved in de novo dTMP biosynthesis. Key enzyme in folate metabolism (By similarity).[PIRNR:PIRNR000389] | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | In various malaria-endemic regions, the appearance of resistance has precluded the use of pyrimidine-based antifolate drugs. Here, a three-step fragment screening was used to identify new non-pyrimidine Plasmodium falciparum dihydrofolate reductase (PfDHFR) inhibitors. Starting from a 1163-fragment commercial library, a two-step differential scanning fluorimetry screen identified 75 primary fragment hits. Subsequent enzyme inhibition assay identified 11 fragments displaying IC50 in the 28-695 muM range and selectivity for PfDHFR. In addition to the known pyrimidine, three new anti-PfDHFR chemotypes were identified. Fragments from each chemotype were successfully co-crystallized with PfDHFR, revealing a binding in the active site, in the vicinity of catalytic residues, which was confirmed by molecular docking on all fragment hits. Finally, comparison with similar non-hit fragments provides preliminary input on available growth vectors for future drug development. | ||
| + | |||
| + | Discovery of new non-pyrimidine scaffolds as Plasmodium falciparum DHFR inhibitors by fragment-based screening.,Hoarau M, Vanichtanankul J, Srimongkolpithak N, Vitsupakorn D, Yuthavong Y, Kamchonwongpaisan S J Enzyme Inhib Med Chem. 2021 Dec;36(1):198-206. doi:, 10.1080/14756366.2020.1854244. PMID:33530764<ref>PMID:33530764</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 7ctz" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
| + | [[Category: Plasmodium falciparum]] | ||
[[Category: Vitsupakorn D]] | [[Category: Vitsupakorn D]] | ||
Current revision
Wild-type plasmodium falciparum dihydrofolate reductase-thymidylate synthase (PfDHFR-TS) complexed with fragment 148, NADPH, and dUMP
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