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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.== |
| - | <StructureSection load='4ew3' size='340' side='right' caption='[[4ew3]], [[Resolution|resolution]] 1.70Å' scene=''> | + | <StructureSection load='4ew3' size='340' side='right'caption='[[4ew3]], [[Resolution|resolution]] 1.70Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <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> | + | <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> |
| - | </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> | + | </td></tr><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> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1njs|1njs]], [[4ew1|4ew1]], [[4ew2|4ew2]]</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=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> |
| - | <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>
| + | |
| - | <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> | + | |
| | </table> | | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/PUR2_HUMAN PUR2_HUMAN] |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Boger, D L]] | + | [[Category: Large Structures]] |
| - | [[Category: Connelly, S]] | + | [[Category: Boger DL]] |
| - | [[Category: DeMartino, K]] | + | [[Category: Connelly S]] |
| - | [[Category: Wilson, I A]] | + | [[Category: DeMartino K]] |
| - | [[Category: Transferase-transferase inhibitor complex]] | + | [[Category: Wilson IA]] |
| Structural highlights
Function
PUR2_HUMAN
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[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Connelly S, Demartino JK, Boger DL, Wilson IA. Biological and Structural Evaluation of 10R- and 10S-Methylthio-DDACTHF Reveals a New Role for Sulfur in Inhibition of Glycinamide Ribonucleotide Transformylase. Biochemistry. 2013 Jul 30;52(30):5133-44. doi: 10.1021/bi4005182. Epub 2013 Jul, 19. PMID:23869564 doi:10.1021/bi4005182
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