2AGT

Aldose Reductase Mutant Leu 300 Pro complexed with Fidarestat

2AGT の概要

• エントリーDOI: 10.2210/pdb2agt/pdb
• 関連するPDBエントリー: 1PWM
• 分子名称: Aldose reductase, CHLORIDE ION, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, ... (6 entities in total)
• 機能のキーワード: oxidoreductase, nadp, fidarestat
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm: P15121
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 37414.78

構造登録者

Petrova, T.,Steuber, H.,Hazemann, I.,Cousido-Siah, A.,Mitschler, A.,Chung, R.,Oka, M.,Klebe, G.,El-Kabbani, O.,Joachimiak, A.,Podjarny, A. (登録日: 2005-07-27, 公開日: 2005-09-20, 最終更新日: 2023-08-23)

主引用文献

Petrova, T.,Steuber, H.,Hazemann, I.,Cousido-Siah, A.,Mitschler, A.,Chung, R.,Oka, M.,Klebe, G.,El-Kabbani, O.,Joachimiak, A.,Podjarny, A.
Factorizing Selectivity Determinants of Inhibitor Binding toward Aldose and Aldehyde Reductases: Structural and Thermodynamic Properties of the Aldose Reductase Mutant Leu300Pro-Fidarestat Complex
J.Med.Chem., 48:5659-5665, 2005

PubMed Abstract: Structure of the Leu300Pro mutant of human aldose reductase (ALR2) in complex with the inhibitor fidarestat is determined. Comparison with the hALR2-fidarestat complex and the porcine aldehyde reductase (ALR1)-fidarestat complex indicates that the hydrogen bond between the Leu300 amino group of the wild-type and the exocyclic amide group of the inhibitor is the key determinant for the specificity of fidarestat for ALR2 over ALR1. Thermodynamic data also suggest an enthalpic contribution as the predominant difference in the binding energy between the aldose reductase mutant and the wild-type. An additional selectivity-determining feature is the difference in the interaction between the inhibitor and the side chain of Trp219, ordered in the present structure but disordered (corresponding Trp220) in the ALR1-fidarestat complex. Thus, the hydrogen bond ( approximately 7 kJ/mol) corresponds to a 23-fold difference in inhibitor potency while the differences in the interactions between Trp219(ALR2) and fidarestat and between Trp220(ALR1) and fidarestat can account for an additional 10-fold difference in potency.

PubMed: 16134934
DOI: 10.1021/jm050424+

実験手法

X-RAY DIFFRACTION (1 Å)