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== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[4ew2]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4EW2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4EW2 FirstGlance]. <br>
<table><tr><td colspan='2'>[[4ew2]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4EW2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4EW2 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DXY:N-({4-[(1S)-4-(2,4-DIAMINO-6-OXO-1,6-DIHYDROPYRIMIDIN-5-YL)-1-(METHYLSULFANYL)BUTYL]PHENYL}CARBONYL)-L-GLUTAMIC+ACID'>DXY</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></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]] 1.602&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DXY:N-({4-[(1S)-4-(2,4-DIAMINO-6-OXO-1,6-DIHYDROPYRIMIDIN-5-YL)-1-(METHYLSULFANYL)BUTYL]PHENYL}CARBONYL)-L-GLUTAMIC+ACID'>DXY</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=4ew2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ew2 OCA], [https://pdbe.org/4ew2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ew2 RCSB], [https://www.ebi.ac.uk/pdbsum/4ew2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ew2 ProSAT]</span></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=4ew2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ew2 OCA], [https://pdbe.org/4ew2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ew2 RCSB], [https://www.ebi.ac.uk/pdbsum/4ew2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ew2 ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
[https://www.uniprot.org/uniprot/PUR2_HUMAN PUR2_HUMAN]  
[https://www.uniprot.org/uniprot/PUR2_HUMAN PUR2_HUMAN]  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Glycinamide ribonucleotide transformylase (GAR Tfase) is a folate-dependent enzyme in the de novo purine biosynthesis pathway, which has long been considered a potential target for development of anti-neoplastic therapeutics. Here we report the biological and X-ray crystallographic evaluations of both independent C10 diastereomers, 10S- and 10R-methylthio-DDACTHF, bound to human GAR Tfase, including the highest-resolution apo GAR Tfase structure to date (1.52 A). Both diastereomers are potent inhibitors (Ki = 210 nM for 10R, and Ki = 180 nM for 10S) of GAR Tfase and exhibit effective inhibition of human leukemia cell growth (IC50 = 80 and 50 nM, respectively). Their inhibitory activity was surprisingly high, and these lipophilic C10-substituted analogues show distinct advantages over their hydrophilic counterparts, most strikingly in retaining potency in mutant human leukemia cell lines that lack reduced folate carrier protein activity (IC50 = 70 and 60 nM, respectively). Structural characterization reveals a new binding mode for these diastereoisomers, in which the lipophilic thiomethyl groups penetrate deeper into a hydrophobic pocket within the folate-binding site. In silico docking simulations of three other sulfur-containing folate analogues also indicate that this hydrophobic cleft represents a favorable region for binding lipophilic substituents. Overall, these results suggest sulfur and its substitutions play an important role in not only the binding of anti-folates to GAR Tfase but also the selectivity and cellular activity (growth inhibition), thereby presenting new possibilities for the future design of potent and selective anti-folate drugs that target GAR Tfase.
Biological and Structural Evaluation of 10R- and 10S-Methylthio-DDACTHF Reveals a New Role for Sulfur in Inhibition of Glycinamide Ribonucleotide Transformylase.,Connelly S, Demartino JK, Boger DL, Wilson IA Biochemistry. 2013 Jul 30;52(30):5133-44. doi: 10.1021/bi4005182. Epub 2013 Jul, 19. PMID:23869564<ref>PMID:23869564</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4ew2" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
</StructureSection>

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