7ctw
From Proteopedia
(Difference between revisions)
| (One intermediate revision not shown.) | |||
| Line 1: | Line 1: | ||
==Wild-type Plasmodium falciparum dihydrofolate reductase-thymidylate synthase (PfDHFR-TS) complexed with fragment 820, NADPH, dUMP== | ==Wild-type Plasmodium falciparum dihydrofolate reductase-thymidylate synthase (PfDHFR-TS) complexed with fragment 820, NADPH, dUMP== | ||
| - | <StructureSection load='7ctw' size='340' side='right'caption='[[7ctw]]' scene=''> | + | <StructureSection load='7ctw' size='340' side='right'caption='[[7ctw]], [[Resolution|resolution]] 2.51Å' 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=7CTW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7CTW FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[7ctw]] 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=7CTW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7CTW 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=7ctw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ctw OCA], [https://pdbe.org/7ctw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ctw RCSB], [https://www.ebi.ac.uk/pdbsum/7ctw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ctw 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]] 2.51Å</td></tr> |
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GEX:1-(2-methylsulfanylphenyl)piperazine'>GEX</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</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=7ctw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ctw OCA], [https://pdbe.org/7ctw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ctw RCSB], [https://www.ebi.ac.uk/pdbsum/7ctw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ctw ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/DRTS_PLAFK DRTS_PLAFK] Bifunctional enzyme. Involved in de novo dTMP biosynthesis. Key enzyme in folate metabolism. Catalyzes an essential reaction for de novo glycine and purine synthesis, DNA precursor synthesis, and for the conversion of dUMP to dTMP.[HAMAP-Rule:MF_00008] | ||
| + | <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 7ctw" style="background-color:#fffaf0;"></div> | ||
| + | |||
| + | ==See Also== | ||
| + | *[[Dihydrofolate reductase 3D structures|Dihydrofolate reductase 3D structures]] | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
| + | [[Category: Plasmodium falciparum]] | ||
[[Category: Vanichtanankul J]] | [[Category: Vanichtanankul J]] | ||
[[Category: Vitsupakorn D]] | [[Category: Vitsupakorn D]] | ||
Current revision
Wild-type Plasmodium falciparum dihydrofolate reductase-thymidylate synthase (PfDHFR-TS) complexed with fragment 820, NADPH, dUMP
| |||||||||||
