1pl0
From Proteopedia
(New page: 200px<br /> <applet load="1pl0" size="450" color="white" frame="true" align="right" spinBox="true" caption="1pl0, resolution 2.6Å" /> '''Crystal structure of...) |
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| - | [[Image:1pl0.gif|left|200px]]<br /> | + | [[Image:1pl0.gif|left|200px]]<br /><applet load="1pl0" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="1pl0" size=" | + | |
caption="1pl0, resolution 2.6Å" /> | caption="1pl0, resolution 2.6Å" /> | ||
'''Crystal structure of human ATIC in complex with folate-based inhibitor, BW2315U89UC'''<br /> | '''Crystal structure of human ATIC in complex with folate-based inhibitor, BW2315U89UC'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Aminoimidazole-4-carboxamide ribonucleotide (AICAR) transformylase/IMP | + | 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== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 1PL0 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with K, AMZ, BW2 and XMP as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http:// | + | 1PL0 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=K:'>K</scene>, <scene name='pdbligand=AMZ:'>AMZ</scene>, <scene name='pdbligand=BW2:'>BW2</scene> and <scene name='pdbligand=XMP:'>XMP</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1PL0 OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Beardsley, G | + | [[Category: Beardsley, G P.]] |
| - | [[Category: Cheong, C | + | [[Category: Cheong, C G.]] |
| - | [[Category: Greasley, S | + | [[Category: Greasley, S E.]] |
| - | [[Category: Horton, P | + | [[Category: Horton, P A.]] |
| - | [[Category: Wilson, I | + | [[Category: Wilson, I A.]] |
[[Category: AMZ]] | [[Category: AMZ]] | ||
[[Category: BW2]] | [[Category: BW2]] | ||
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[[Category: xanthosine monophosphate]] | [[Category: xanthosine monophosphate]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:29:53 2008'' |
Revision as of 12:29, 21 February 2008
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Crystal structure of human ATIC in complex with folate-based inhibitor, BW2315U89UC
Contents |
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.
Disease
Known diseases associated with this structure: AICA-ribosiduria due to ATIC deficiency OMIM:[601731]
About this Structure
1PL0 is a Single protein structure of sequence from Homo sapiens with , , and as ligands. 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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