1SD2

STRUCTURE OF HUMAN 5'-DEOXY-5'-METHYLTHIOADENOSINE PHOSPHORYLASE COMPLEXED WITH 5'-METHYLTHIOTUBERCIDIN

1SD2 の概要

• エントリーDOI: 10.2210/pdb1sd2/pdb
• 分子名称: 5'-methylthioadenosine phosphorylase, SULFATE ION, 2-(4-AMINO-PYRROLO[2,3-D]PYRIMIDIN-7-YL)-5-METHYLSULFANYLMETHYL-TETRAHYDRO-FURAN-3,4-DIOL, ... (4 entities in total)
• 機能のキーワード: methylthioadenosine phosphorylase, purine nucleoside phosphorylase, purine salvage, 5'-methylthiotubercidin, mtt, sulfate, transferase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm: Q13126
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 31669.46

構造登録者

Lee, J.E.,Settembre, E.C.,Cornell, K.A.,Riscoe, M.K.,Sufrin, J.R.,Ealick, S.E.,Howell, P.L. (登録日: 2004-02-12, 公開日: 2004-05-18, 最終更新日: 2024-02-14)

主引用文献

Lee, J.E.,Settembre, E.C.,Cornell, K.A.,Riscoe, M.K.,Sufrin, J.R.,Ealick, S.E.,Howell, P.L.
Structural Comparison of MTA Phosphorylase and MTA/AdoHcy Nucleosidase Explains Substrate Preferences and Identifies Regions Exploitable for Inhibitor Design.
Biochemistry, 43:5159-5169, 2004

PubMed Abstract: The development of new and effective antiprotozoal drugs has been a difficult challenge because of the close similarity of the metabolic pathways between microbial and mammalian systems. 5'-Methylthioadenosine/S-adenosylhomocysteine (MTA/AdoHcy) nucleosidase is thought to be an ideal target for therapeutic drug design as the enzyme is present in many microbes but not in mammals. MTA/AdoHcy nucleosidase (MTAN) irreversibly depurinates MTA or AdoHcy to form adenine and the corresponding thioribose. The inhibition of MTAN leads to a buildup of toxic byproducts that affect various microbial pathways such as quorum sensing, biological methylation, polyamine biosynthesis, and methionine recycling. The design of nucleosidase-specific inhibitors is complicated by its structural similarity to the human MTA phosphorylase (MTAP). The crystal structures of human MTAP complexed with formycin A and 5'-methylthiotubercidin have been solved to 2.0 and 2.1 A resolution, respectively. Comparisons of the MTAP and MTAN inhibitor complexes reveal size and electrostatic potential differences in the purine, ribose, and 5'-alkylthio binding sites, which account for the substrate specificity and reactions catalyzed. In addition, the differences between the two enzymes have allowed the identification of exploitable regions that can be targeted for the development of high-affinity nucleosidase-specific inhibitors. Sequence alignments of Escherichia coli MTAN, human MTAP, and plant MTA nucleosidases also reveal potential structural changes to the 5'-alkylthio binding site that account for the substrate preference of plant MTA nucleosidases.

PubMed: 15122881
DOI: 10.1021/bi035492h

実験手法

X-RAY DIFFRACTION (2.1 Å)