1P4R

Crystal Structure of Human ATIC in complex with folate-based inhibitor BW1540U88UD

1P4R の概要

• エントリーDOI: 10.2210/pdb1p4r/pdb
• 分子名称: Bifunctional purine biosynthesis protein PURH, POTASSIUM ION, AMINOIMIDAZOLE 4-CARBOXAMIDE RIBONUCLEOTIDE, ... (6 entities in total)
• 機能のキーワード: antifolate, atic, purine biosynthesis, bw1540u88ud, transferase, hydrolase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 131494.25

構造登録者

Cheong, C.-G.,Greasley, S.E.,Horton, P.A.,Beardsley, G.P.,Wilson, I.A. (登録日: 2003-04-23, 公開日: 2004-03-30, 最終更新日: 2023-08-16)

主引用文献

Cheong, C.-G.,Wolan, D.W.,Greasley, S.E.,Horton, P.A.,Beardsley, G.P.,Wilson, I.A.
Crystal structures of human bifunctional enzyme aminoimidazole-4-carboxamide ribonucleotide transformylase/IMP cyclohydrolase in complex with potent sulfonyl-containing antifolates
J.Biol.Chem., 279:18034-18045, 2004

PubMed Abstract: 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.

PubMed: 14966129
DOI: 10.1074/jbc.M313691200

実験手法

X-RAY DIFFRACTION (2.55 Å)