4ew3

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==The structure of human glycinamide ribonucleotide transformylase in complex with 10R-methylthio-DDATHF.==
==The structure of human glycinamide ribonucleotide transformylase in complex with 10R-methylthio-DDATHF.==
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<StructureSection load='4ew3' size='340' side='right' caption='[[4ew3]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
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<StructureSection load='4ew3' size='340' side='right'caption='[[4ew3]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[4ew3]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4EW3 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4EW3 FirstGlance]. <br>
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<table><tr><td colspan='2'>[[4ew3]] 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=4EW3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4EW3 FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DXZ:N-({4-[(1R)-4-(2,4-DIAMINO-6-OXO-1,6-DIHYDROPYRIMIDIN-5-YL)-1-(METHYLSULFANYL)BUTYL]PHENYL}CARBONYL)-L-GLUTAMIC+ACID'>DXZ</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.702&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1njs|1njs]], [[4ew1|4ew1]], [[4ew2|4ew2]]</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DXZ:N-({4-[(1R)-4-(2,4-DIAMINO-6-OXO-1,6-DIHYDROPYRIMIDIN-5-YL)-1-(METHYLSULFANYL)BUTYL]PHENYL}CARBONYL)-L-GLUTAMIC+ACID'>DXZ</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">GART, PGFT, PRGS ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4ew3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ew3 OCA], [https://pdbe.org/4ew3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ew3 RCSB], [https://www.ebi.ac.uk/pdbsum/4ew3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ew3 ProSAT]</span></td></tr>
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<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=4ew3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ew3 OCA], [http://pdbe.org/4ew3 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4ew3 RCSB], [http://www.ebi.ac.uk/pdbsum/4ew3 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4ew3 ProSAT]</span></td></tr>
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</table>
</table>
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<div style="background-color:#fffaf0;">
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== Function ==
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== Publication Abstract from PubMed ==
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[https://www.uniprot.org/uniprot/PUR2_HUMAN PUR2_HUMAN]
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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.
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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>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 4ew3" style="background-color:#fffaf0;"></div>
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== References ==
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<references/>
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Human]]
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[[Category: Homo sapiens]]
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[[Category: Boger, D L]]
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[[Category: Large Structures]]
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[[Category: Connelly, S]]
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[[Category: Boger DL]]
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[[Category: DeMartino, K]]
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[[Category: Connelly S]]
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[[Category: Wilson, I A]]
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[[Category: DeMartino K]]
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[[Category: Transferase-transferase inhibitor complex]]
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[[Category: Wilson IA]]

Current revision

The structure of human glycinamide ribonucleotide transformylase in complex with 10R-methylthio-DDATHF.

PDB ID 4ew3

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