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5uz0

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Revision as of 08:27, 30 September 2020

Crystal structure of AICARFT bound to an antifolate

Structural highlights

5uz0 is a 4 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
Related:	5uy8
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[PUR9_HUMAN] Defects in ATIC are the cause of AICAR transformylase/IMP cyclohydrolase deficiency (AICAR) [MIM: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.^[1] ^[2]

Function

[PUR9_HUMAN] Bifunctional enzyme that catalyzes 2 steps in purine biosynthesis.^[3]

Publication Abstract from PubMed

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.

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^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Cheong CG, Wolan DW, Greasley SE, Horton PA, Beardsley GP, Wilson IA. Crystal structures of human bifunctional enzyme aminoimidazole-4-carboxamide ribonucleotide transformylase/IMP cyclohydrolase in complex with potent sulfonyl-containing antifolates. J Biol Chem. 2004 Apr 23;279(17):18034-45. Epub 2004 Feb 13. PMID:14966129 doi:10.1074/jbc.M313691200
↑ Marie S, Heron B, Bitoun P, Timmerman T, Van Den Berghe G, Vincent MF. AICA-ribosiduria: a novel, neurologically devastating inborn error of purine biosynthesis caused by mutation of ATIC. Am J Hum Genet. 2004 Jun;74(6):1276-81. Epub 2004 Apr 26. PMID:15114530 doi:10.1086/421475
↑ Cheong CG, Wolan DW, Greasley SE, Horton PA, Beardsley GP, Wilson IA. Crystal structures of human bifunctional enzyme aminoimidazole-4-carboxamide ribonucleotide transformylase/IMP cyclohydrolase in complex with potent sulfonyl-containing antifolates. J Biol Chem. 2004 Apr 23;279(17):18034-45. Epub 2004 Feb 13. PMID:14966129 doi:10.1074/jbc.M313691200
↑ 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. 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. J Med Chem. 2017 Dec 14;60(23):9599-9616. doi: 10.1021/acs.jmedchem.7b01046. Epub, 2017 Nov 9. PMID:29072452 doi:http://dx.doi.org/10.1021/acs.jmedchem.7b01046

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5uz0"

@@ Line 1: / Line 1: @@
 ==Crystal structure of AICARFT bound to an antifolate==
-<StructureSection load='5uz0' size='340' side='right' caption='[[5uz0]], [[Resolution|resolution]] 1.79&Aring;' scene=''>
+<StructureSection load='5uz0' size='340' side='right'caption='[[5uz0]], [[Resolution|resolution]] 1.79&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5uz0]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5UZ0 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5UZ0 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5uz0]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5UZ0 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5UZ0 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=8US:N-(6-fluoro-1-oxo-1,2-dihydroisoquinolin-7-yl)-5-[(3R)-3-hydroxypyrrolidin-1-yl]thiophene-2-sulfonamide'>8US</scene>, <scene name='pdbligand=AMZ:AMINOIMIDAZOLE+4-CARBOXAMIDE+RIBONUCLEOTIDE'>AMZ</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=8US:N-(6-fluoro-1-oxo-1,2-dihydroisoquinolin-7-yl)-5-[(3R)-3-hydroxypyrrolidin-1-yl]thiophene-2-sulfonamide'>8US</scene>, <scene name='pdbligand=AMZ:AMINOIMIDAZOLE+4-CARBOXAMIDE+RIBONUCLEOTIDE'>AMZ</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5uy8|5uy8]]</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=5uz0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5uz0 OCA], [http://pdbe.org/5uz0 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5uz0 RCSB], [http://www.ebi.ac.uk/pdbsum/5uz0 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5uz0 ProSAT]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5uz0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5uz0 OCA], [http://pdbe.org/5uz0 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5uz0 RCSB], [http://www.ebi.ac.uk/pdbsum/5uz0 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5uz0 ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 21: / Line 21: @@
 </div>
 <div class="pdbe-citations 5uz0" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Bifunctional purine biosynthesis protein PURH|Bifunctional purine biosynthesis protein PURH]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Large Structures]]
 [[Category: Atwell, S]]
 [[Category: Clawson, D]]

5uz0

From Proteopedia

Revision as of 08:27, 30 September 2020

Crystal structure of AICARFT bound to an antifolate

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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