4Q3T

Crystal structure of Schistosoma mansoni arginase in complex with inhibitor NOHA

4Q3T の概要

• エントリーDOI: 10.2210/pdb4q3t/pdb
• 関連するPDBエントリー: 4Q3P 4Q3Q 4Q3R 4Q3S 4Q3U 4Q3V 4Q40 4Q41 4Q42
• 分子名称: Arginase, MANGANESE (II) ION, GLYCEROL, ... (5 entities in total)
• 機能のキーワード: arginase-deacetylase fold, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Schistosoma mansoni (Blood fluke)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 170822.04

構造登録者

Hai, Y.,Edwards, J.E.,Van Zandt, M.C.,Hoffmann, K.F.,Christianson, D.W. (登録日: 2014-04-12, 公開日: 2014-07-16, 最終更新日: 2023-09-20)

主引用文献

Hai, Y.,Edwards, J.E.,Van Zandt, M.C.,Hoffmann, K.F.,Christianson, D.W.
Crystal Structure of Schistosoma mansoni Arginase, a Potential Drug Target for the Treatment of Schistosomiasis.
Biochemistry, 53:4671-4684, 2014

PubMed Abstract: The X-ray crystal structure of arginase from Schistosoma mansoni (SmARG) and the structures of its complexes with several amino acid inhibitors have been determined at atomic resolution. SmARG is a binuclear manganese metalloenzyme that catalyzes the hydrolysis of l-arginine to form l-ornithine and urea, and this enzyme is upregulated in all forms of the parasite that interact with the human host. Current hypotheses suggest that parasitic arginases could play a role in host immune evasion by depleting pools of substrate l-arginine that would otherwise be utilized for NO biosynthesis and NO-dependent processes in the immune response. Although the amino acid sequence of SmARG is only 42% identical with that of human arginase I, residues important for substrate binding and catalysis are strictly conserved. In general, classical amino acid inhibitors such as 2(S)-amino-6-boronohexanoic acid (ABH) tend to bind more weakly to SmARG than to human arginase I despite identical inhibitor binding modes in each enzyme active site. The identification of a patch on the enzyme surface capable of accommodating the additional Cα substitutent of an α,α-disubstituted amino acid inhibitor suggests that such inhibitors could exhibit higher affinity and biological activity. The structures of SmARG complexed with two different α,α-disubstituted derivatives of ABH are presented and provide a proof of concept for this approach in the enhancement of enzyme-inhibitor affinity.

PubMed: 25007099
DOI: 10.1021/bi5004519

実験手法

X-RAY DIFFRACTION (2.142 Å)