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| | <StructureSection load='1p4r' size='340' side='right'caption='[[1p4r]], [[Resolution|resolution]] 2.55Å' scene=''> | | <StructureSection load='1p4r' size='340' side='right'caption='[[1p4r]], [[Resolution|resolution]] 2.55Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[1p4r]] is a 2 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=1P4R OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=1P4R FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[1p4r]] is a 2 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=1P4R OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1P4R FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=354:N-[(S)-(4-{[(2-AMINO-4-HYDROXYQUINAZOLIN-6-YL)(DIHYDROXY)-LAMBDA~4~-SULFANYL]AMINO}PHENYL)(HYDROXY)METHYL]-L-GLUTAMIC+ACID'>354</scene>, <scene name='pdbligand=AMZ:AMINOIMIDAZOLE+4-CARBOXAMIDE+RIBONUCLEOTIDE'>AMZ</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=XMP:XANTHOSINE-5-MONOPHOSPHATE'>XMP</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]] 2.55Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ATIC cDNA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=354:N-[(S)-(4-{[(2-AMINO-4-HYDROXYQUINAZOLIN-6-YL)(DIHYDROXY)-LAMBDA~4~-SULFANYL]AMINO}PHENYL)(HYDROXY)METHYL]-L-GLUTAMIC+ACID'>354</scene>, <scene name='pdbligand=AMZ:AMINOIMIDAZOLE+4-CARBOXAMIDE+RIBONUCLEOTIDE'>AMZ</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=XMP:XANTHOSINE-5-MONOPHOSPHATE'>XMP</scene></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=1p4r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1p4r OCA], [http://pdbe.org/1p4r PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1p4r RCSB], [http://www.ebi.ac.uk/pdbsum/1p4r PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=1p4r 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=1p4r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1p4r OCA], [https://pdbe.org/1p4r PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1p4r RCSB], [https://www.ebi.ac.uk/pdbsum/1p4r PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1p4r ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[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> | + | [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 == |
| - | [[http://www.uniprot.org/uniprot/PUR9_HUMAN PUR9_HUMAN]] Bifunctional enzyme that catalyzes 2 steps in purine biosynthesis.<ref>PMID:14966129</ref> | + | [https://www.uniprot.org/uniprot/PUR9_HUMAN PUR9_HUMAN] Bifunctional enzyme that catalyzes 2 steps in purine biosynthesis.<ref>PMID:14966129</ref> |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Beardsley, G P]] | + | [[Category: Beardsley GP]] |
| - | [[Category: Cheong, C G]] | + | [[Category: Cheong C-G]] |
| - | [[Category: Greasley, S E]] | + | [[Category: Greasley SE]] |
| - | [[Category: Horton, P A]] | + | [[Category: Horton PA]] |
| - | [[Category: Wilson, I A]] | + | [[Category: Wilson IA]] |
| - | [[Category: Antifolate]]
| + | |
| - | [[Category: Atic]]
| + | |
| - | [[Category: Bw1540u88ud]]
| + | |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Purine biosynthesis]]
| + | |
| - | [[Category: Transferase]]
| + | |
| Structural highlights
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]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Aminoimidazole-4-carboxamide ribonucleotide (AICAR) transformylase/IMP cyclohydrolase (ATIC) is a bifunctional enzyme with folate-dependent AICAR transformylase and IMP cyclohydrolase activities that catalyzes the last two steps of purine biosynthesis. The AICAR transformylase inhibitors BW1540 and BW2315 are sulfamido-bridged 5,8-dideazafolate analogs with remarkably potent K(i) values of 8 and 6 nm, respectively, compared with most other antifolates. Crystal structures of ATIC at 2.55 and 2.60 A with each inhibitor, in the presence of substrate AICAR, revealed that the sulfonyl groups dominate inhibitor binding and orientation through interaction with the proposed oxyanion hole. These agents then appear to mimic the anionic transition state and now implicate Asn(431') in the reaction mechanism along with previously identified key catalytic residues Lys(266) and His(267). Potent and selective inhibition of the AICAR transformylase active site, compared with other folate-dependent enzymes, should therefore be pursued by further design of sulfonyl-containing antifolates.
Crystal structures of human bifunctional enzyme aminoimidazole-4-carboxamide ribonucleotide transformylase/IMP cyclohydrolase in complex with potent sulfonyl-containing antifolates.,Cheong CG, Wolan DW, Greasley SE, Horton PA, Beardsley GP, Wilson IA J Biol Chem. 2004 Apr 23;279(17):18034-45. Epub 2004 Feb 13. PMID:14966129[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
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
- ↑ 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
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