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5uy8

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==Crystal structure of AICARFT bound to an antifolate==
==Crystal structure of AICARFT bound to an antifolate==
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<StructureSection load='5uy8' size='340' side='right' caption='[[5uy8]], [[Resolution|resolution]] 2.39&Aring;' scene=''>
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<StructureSection load='5uy8' size='340' side='right'caption='[[5uy8]], [[Resolution|resolution]] 2.39&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[5uy8]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5UY8 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5UY8 FirstGlance]. <br>
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<table><tr><td colspan='2'>[[5uy8]] is a 4 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=5UY8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5UY8 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=8UM:5-[(5S)-5-ethyl-5-methyl-6-oxo-1,4,5,6-tetrahydropyridin-3-yl]-N-(6-fluoro-1-oxo-1,2-dihydroisoquinolin-7-yl)thiophene-2-sulfonamide'>8UM</scene>, <scene name='pdbligand=AMZ:AMINOIMIDAZOLE+4-CARBOXAMIDE+RIBONUCLEOTIDE'>AMZ</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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]] 2.39&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5uz0|5uz0]]</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=8UM:5-[(5S)-5-ethyl-5-methyl-6-oxo-1,4,5,6-tetrahydropyridin-3-yl]-N-(6-fluoro-1-oxo-1,2-dihydroisoquinolin-7-yl)thiophene-2-sulfonamide'>8UM</scene>, <scene name='pdbligand=AMZ:AMINOIMIDAZOLE+4-CARBOXAMIDE+RIBONUCLEOTIDE'>AMZ</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></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=5uy8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5uy8 OCA], [http://pdbe.org/5uy8 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5uy8 RCSB], [http://www.ebi.ac.uk/pdbsum/5uy8 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5uy8 ProSAT]</span></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=5uy8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5uy8 OCA], [https://pdbe.org/5uy8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5uy8 RCSB], [https://www.ebi.ac.uk/pdbsum/5uy8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5uy8 ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
== Disease ==
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[[http://www.uniprot.org/uniprot/PUR9_HUMAN PUR9_HUMAN]] Defects in ATIC are the cause of AICAR transformylase/IMP cyclohydrolase deficiency (AICAR) [MIM:[http://omim.org/entry/608688 608688]]. A neurologically devastating inborn error of purine biosynthesis. Patients excrete massive amounts of AICA-riboside in the urine and accumulate AICA-ribotide and its derivatives in erythrocytes and fibroblasts. AICAR causes profound mental retardation, epilepsy, dysmorphic features and congenital blindness.<ref>PMID:14966129</ref> <ref>PMID:15114530</ref>
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[https://www.uniprot.org/uniprot/PUR9_HUMAN PUR9_HUMAN] Defects in ATIC are the cause of AICAR transformylase/IMP cyclohydrolase deficiency (AICAR) [MIM:[https://omim.org/entry/608688 608688]. A neurologically devastating inborn error of purine biosynthesis. Patients excrete massive amounts of AICA-riboside in the urine and accumulate AICA-ribotide and its derivatives in erythrocytes and fibroblasts. AICAR causes profound mental retardation, epilepsy, dysmorphic features and congenital blindness.<ref>PMID:14966129</ref> <ref>PMID:15114530</ref>
== Function ==
== Function ==
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[[http://www.uniprot.org/uniprot/PUR9_HUMAN PUR9_HUMAN]] Bifunctional enzyme that catalyzes 2 steps in purine biosynthesis.<ref>PMID:14966129</ref>
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[https://www.uniprot.org/uniprot/PUR9_HUMAN PUR9_HUMAN] Bifunctional enzyme that catalyzes 2 steps in purine biosynthesis.<ref>PMID:14966129</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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A hallmark of cancer is unbridled proliferation that can result in increased demand for de novo synthesis of purine and pyrimidine bases required for DNA and RNA biosynthesis. These synthetic pathways are frequently upregulated in cancer and involve various folate-dependent enzymes. Antifolates have a proven record as clinically used oncolytic agents. Our recent research efforts have produced LSN 3213128 (compound 28a), a novel, selective, nonclassical, orally bioavailable antifolate with potent and specific inhibitory activity for aminoimidazole-4-carboxamide ribonucleotide formyltransferase (AICARFT), an enzyme in the purine biosynthetic pathway. Inhibition of AICARFT with compound 28a results in dramatic elevation of 5-aminoimidazole 4-carboxamide ribonucleotide (ZMP) and growth inhibition in NCI-H460 and MDA-MB-231met2 cancer cell lines. Treatment with this inhibitor in a murine based xenograft model of triple negative breast cancer (TNBC) resulted in tumor growth inhibition.
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Discovery of N-(6-Fluoro-1-oxo-1,2-dihydroisoquinolin-7-yl)-5-[(3R)-3-hydroxypyrrolidin-1-yl]t hiophene-2-sulfonamide (LSN 3213128), a Potent and Selective Nonclassical Antifolate Aminoimidazole-4-carboxamide Ribonucleotide Formyltransferase (AICARFT) Inhibitor Effective at Tumor Suppression in a Cancer Xenograft Model.,Fales KR, Njoroge FG, Brooks HB, Thibodeaux S, Torrado A, Si C, Toth JL, Mc Cowan JR, Roth KD, Thrasher KJ, Frimpong K, Lee MR, Dally RD, Shepherd TA, Durham TB, Margolis BJ, Wu Z, Wang Y, Atwell S, Wang J, Hui YH, Meier TI, Konicek SA, Geeganage S J Med Chem. 2017 Dec 14;60(23):9599-9616. doi: 10.1021/acs.jmedchem.7b01046. Epub, 2017 Nov 9. PMID:29072452<ref>PMID:29072452</ref>
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==See Also==
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*[[Bifunctional purine biosynthesis protein PURH|Bifunctional purine biosynthesis protein PURH]]
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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 5uy8" style="background-color:#fffaf0;"></div>
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== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Atwell, S]]
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[[Category: Homo sapiens]]
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[[Category: Clawson, D]]
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[[Category: Large Structures]]
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[[Category: Fales, K R]]
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[[Category: Atwell S]]
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[[Category: Wang, J]]
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[[Category: Clawson D]]
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[[Category: Wang, Y]]
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[[Category: Fales KR]]
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[[Category: Aicar]]
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[[Category: Wang J]]
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[[Category: Aicarft]]
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[[Category: Wang Y]]
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[[Category: Amz]]
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[[Category: Hydrolase]]
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[[Category: Transferase]]
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Current revision

Crystal structure of AICARFT bound to an antifolate

PDB ID 5uy8

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