1ME8

Inosine Monophosphate Dehydrogenase (IMPDH) From Tritrichomonas Foetus with RVP bound

1ME8 の概要

• エントリーDOI: 10.2210/pdb1me8/pdb
• 関連するPDBエントリー: 1AK5 1ME7 1ME9 1MEH 1MEI 1MEW
• 分子名称: INOSINE-5'-MONOPHOSPHATE DEHYDROGENASE, POTASSIUM ION, SODIUM ION, ... (5 entities in total)
• 機能のキーワード: alpha beta barrel, oxidoreductase
• 由来する生物種: Tritrichomonas foetus
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 55942.28

構造登録者

Prosise, G.L.,Wu, J.,Luecke, H. (登録日: 2002-08-08, 公開日: 2003-01-14, 最終更新日: 2024-10-30)

主引用文献

Prosise, G.L.,Wu, J.,Luecke, H.
Crystal Structure of Tritrichomonas foetus Inosine Monophosphate Dehydrogenase in Complex with the Inhibitor Ribavirin Monophosphate Reveals a Catalysis-dependent Ion-binding Site
J.Biol.Chem., 277:50654-50659, 2002

PubMed Abstract: Inosine monophosphate dehydrogenase (IMPDH) catalyzes the rate-limiting step in GMP biosynthesis. The resulting intracellular pool of guanine nucleotides is of great importance to all cells for use in DNA and RNA synthesis, metabolism, and signal transduction. The enzyme binds IMP and the cofactor NAD(+) in random order, IMP is converted to XMP, NAD(+) is reduced to NADH, and finally, NADH and then XMP are released sequentially. XMP is subsequently converted into GMP by GMP synthetase. Drugs that decrease GMP synthesis by inhibiting IMPDH have been shown to have antiproliferative as well as antiviral activity. Several drugs are in use that target the substrate- or cofactor-binding site; however, due to differences between the mammalian and microbial isoforms, most drugs are far less effective against the microbial form of the enzyme than the mammalian form. The high resolution crystal structures of the protozoan parasite Tritrichomonas foetus IMPDH complexed with the inhibitor ribavirin monophosphate as well as monophosphate together with a second inhibitor, mycophenolic acid, are presented here. These structures reveal an active site cation identified previously only in the Chinese hamster IMPDH structure with covalently bound IMP. This cation was not found previously in apo IMPDH, IMPDH in complex with XMP, or covalently bound inhibitor, indicating that the cation-binding site may be catalysis-dependent. A comparison of T. foetus IMPDH with the Chinese hamster and Streptococcus pyogenes structures reveals differences in the active site loop architecture, which contributes to differences in cation binding during the catalytic sequence and the kinetic rates between bacterial, protozoan, and mammalian enzymes. Exploitation of these differences may lead to novel inhibitors, which favor the microbial form of the enzyme.

PubMed: 12235158
DOI: 10.1074/jbc.M208330200

実験手法

X-RAY DIFFRACTION (1.9 Å)