1p4r
From Proteopedia
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'''Crystal Structure of Human ATIC in complex with folate-based inhibitor BW1540U88UD''' | '''Crystal Structure of Human ATIC in complex with folate-based inhibitor BW1540U88UD''' | ||
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[[Category: Horton, P A.]] | [[Category: Horton, P A.]] | ||
[[Category: Wilson, I A.]] | [[Category: Wilson, I A.]] | ||
| - | [[Category: | + | [[Category: Antifolate]] |
| - | [[Category: | + | [[Category: Atic]] |
| - | [[Category: | + | [[Category: Bw1540u88ud]] |
| - | [[Category: | + | [[Category: Purine biosynthesis]] |
| - | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 04:41:10 2008'' | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | |
Revision as of 01:41, 3 May 2008
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 Page seeded by OCA on Sat May 3 04:41:10 2008
