1p4r
From Proteopedia
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|PDB= 1p4r |SIZE=350|CAPTION= <scene name='initialview01'>1p4r</scene>, resolution 2.55Å | |PDB= 1p4r |SIZE=350|CAPTION= <scene name='initialview01'>1p4r</scene>, resolution 2.55Å | ||
|SITE= | |SITE= | ||
| - | |LIGAND= | + | |LIGAND= <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> |
|ACTIVITY= | |ACTIVITY= | ||
|GENE= ATIC cDNA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | |GENE= ATIC cDNA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | ||
| + | |DOMAIN= | ||
| + | |RELATEDENTRY= | ||
| + | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1p4r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1p4r OCA], [http://www.ebi.ac.uk/pdbsum/1p4r PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1p4r RCSB]</span> | ||
}} | }} | ||
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==Overview== | ==Overview== | ||
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. | 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. | ||
| - | |||
| - | ==Disease== | ||
| - | Known diseases associated with this structure: AICA-ribosiduria due to ATIC deficiency OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601731 601731]] | ||
==About this Structure== | ==About this Structure== | ||
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[[Category: Horton, P A.]] | [[Category: Horton, P A.]] | ||
[[Category: Wilson, I A.]] | [[Category: Wilson, I A.]] | ||
| - | [[Category: 354]] | ||
| - | [[Category: AMZ]] | ||
| - | [[Category: K]] | ||
| - | [[Category: XMP]] | ||
[[Category: antifolate]] | [[Category: antifolate]] | ||
[[Category: atic]] | [[Category: atic]] | ||
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[[Category: purine biosynthesis]] | [[Category: purine biosynthesis]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Mar | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Mar 30 22:54:50 2008'' |
Revision as of 19:54, 30 March 2008
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| , resolution 2.55Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | , , , | ||||||
| Gene: | ATIC cDNA (Homo sapiens) | ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
Crystal Structure of Human ATIC in complex with folate-based inhibitor BW1540U88UD
Overview
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.
About this Structure
1P4R is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
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
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