4IXV

Crystal structure of human Arginase-2 complexed with inhibitor 2d: {(5R)-5-amino-5-carboxy-5-[1-(4-chlorobenzyl)piperidin-4-yl]pentyl}(trihydroxy)borate(1-)

4IXV の概要

• エントリーDOI: 10.2210/pdb4ixv/pdb
• 関連するPDBエントリー: 1D3V 1PQ3 4IXU
• 分子名称: Arginase-2, mitochondrial, MANGANESE (II) ION, BENZAMIDINE, ... (6 entities in total)
• 機能のキーワード: metalloenzyme, alpha/beta fold, hydrolase, arginine metabolism, mitochondrion, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens
• 細胞内の位置: Mitochondrion : P78540
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 101818.54

構造登録者

Cousido-Siah, A.,Mitschler, A.,Ruiz, F.X.,Whitehouse, D.,Beckett, P.,Van Zandt, M.C.,Ji, M.K.,Ryder, T.,Jagdmann, R.,Andreoli, M.,Olczak, J.,Mazur, M.,Czestkowski, W.,Piotrowska, W.,Schroeter, H.,Golebiowski, A.,Podjarny, A. (登録日: 2013-01-28, 公開日: 2013-12-11, 最終更新日: 2023-09-20)

主引用文献

Golebiowski, A.,Whitehouse, D.,Beckett, R.P.,Van Zandt, M.,Ji, M.K.,Ryder, T.R.,Jagdmann, E.,Andreoli, M.,Lee, Y.,Sheeler, R.,Conway, B.,Olczak, J.,Mazur, M.,Czestkowski, W.,Piotrowska, W.,Cousido-Siah, A.,Ruiz, F.X.,Mitschler, A.,Podjarny, A.,Schroeter, H.
Synthesis of quaternary alpha-amino acid-based arginase inhibitors via the Ugi reaction.
Bioorg.Med.Chem.Lett., 23:4837-4841, 2013

PubMed Abstract: The Ugi reaction has been successfully applied to the synthesis of novel arginase inhibitors. In an effort to decrease conformational flexibility of the previously reported series of 2-amino-6-boronohexanoic acid (ABH) analogs 1, we designed and synthesized a series of compounds, 2, in which a piperidine ring is linked directly to a quaternary amino acid center. Further improvement of in vitro activity was achieved by adding two carbon bridge in the piperidine ring, that is, tropane analogs 11. These improvements in activity are rationalized by X-ray crystallography analysis, which show that the tropane ring nitrogen atom moves into direct contact with Asp202 (arginase II numbering). The synthetic routes described here enabled the design of novel arginase inhibitors with improved potency and markedly different physico-chemical properties compared to ABH. Compound 11c represents the most in vitro active arginase inhibitor reported to date.

PubMed: 23886684
DOI: 10.1016/j.bmcl.2013.06.092

実験手法

X-RAY DIFFRACTION (2.3 Å)