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| {{STRUCTURE_1pl0| PDB=1pl0 | SCENE= }} | | {{STRUCTURE_1pl0| PDB=1pl0 | SCENE= }} |
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| '''Crystal structure of human ATIC in complex with folate-based inhibitor, BW2315U89UC'''
| | ===Crystal structure of human ATIC in complex with folate-based inhibitor, BW2315U89UC=== |
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| ==Overview==
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| 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.
| | The line below this paragraph, {{ABSTRACT_PUBMED_14966129}}, adds the Publication Abstract to the page |
| | (as it appears on PubMed at http://www.pubmed.gov), where 14966129 is the PubMed ID number. |
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| | {{ABSTRACT_PUBMED_14966129}} |
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| ==Disease== | | ==Disease== |
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| [[Category: Imp cyclohydrolase]] | | [[Category: Imp cyclohydrolase]] |
| [[Category: Xanthosine monophosphate]] | | [[Category: Xanthosine monophosphate]] |
| ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 05:12:19 2008'' | | |
| | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 11:43:32 2008'' |
