2ON3

A structural insight into the inhibition of human and Leishmania donovani ornithine decarboxylases by 3-aminooxy-1-aminopropane

2ON3 の概要

• エントリーDOI: 10.2210/pdb2on3/pdb
• 関連するPDBエントリー: 2OO0
• 分子名称: Ornithine decarboxylase, 3-AMINOOXY-1-AMINOPROPANE (2 entities in total)
• 機能のキーワード: beta-alpha-barrel, sheet, lyase
• 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: 102586.29

構造登録者

Dufe, V.T.,Ingner, D.,Heby, O.,Khomutov, A.R.,Persson, L.,Al-Karadaghi, S. (登録日: 2007-01-23, 公開日: 2007-07-17, 最終更新日: 2023-12-27)

主引用文献

Dufe, V.T.,Ingner, D.,Heby, O.,Khomutov, A.R.,Persson, L.,Al-Karadaghi, S.
A structural insight into the inhibition of human and Leishmania donovani ornithine decarboxylases by 1-amino-oxy-3-aminopropane.
Biochem.J., 405:261-268, 2007

PubMed Abstract: The critical role of polyamines in key processes such as cell growth, differentiation and macromolecular synthesis makes the enzymes involved in their synthesis potential targets in the treatment of certain types of cancer and parasitic diseases. Here we present a study on the inhibition of human and Leishmania donovani ODC (ornithine decarboxylase), the first committed enzyme in the polyamine biosynthesis pathway, by APA (1-amino-oxy-3-aminopropane). The present study shows APA to be a potent inhibitor of both human and L. donovani ODC with a K(i) value of around 1.0 nM. We also show that L. donovani ODC binds the substrate, the co-enzyme pyridoxal 5'-phosphate and the irreversible inhibitor alpha-difluoromethylornithine (a curative agent of West African sleeping sickness) with less affinity than human ODC. We have also determined the three-dimensional structure of human ODC in complex with APA, which revealed the mode of the inhibitor binding to the enzyme. In contrast with earlier reports, the structure showed no indication of oxime formation between APA and PLP (pyridoxal 5'-phosphate). Homology modelling suggests a similar mode of binding of APA to L. donovani ODC. A comparison of the ODC-APA-PLP structure with earlier ODC structures also shows that the protease-sensitive loop (residues 158-168) undergoes a large conformational change and covers the active site of the protein. The understanding of the structural mode of APA binding may constitute the basis for the development of more specific inhibitors of L. donovani ODC.

PubMed: 17407445
DOI: 10.1042/BJ20070188

実験手法

X-RAY DIFFRACTION (3 Å)