1US0

Human Aldose Reductase in complex with NADP+ and the inhibitor IDD594 at 0.66 Angstrom

1US0 の概要

• エントリーDOI: 10.2210/pdb1us0/pdb
• 関連するPDBエントリー: 1ABN 1ADS 1AZ1 1AZ2 1EF3 1EL3 1IEI 1MAR 2ACQ 2ACR 2ACS 2ACU
• 分子名称: ALDOSE REDUCTASE, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, IDD594, ... (5 entities in total)
• 機能のキーワード: oxidoreductase, nadp, idd594
• 由来する生物種: HOMO SAPIENS (HUMAN)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 37444.25

構造登録者

Howard, E.I.,Sanishvili, R.,Cachau, R.E.,Mitschler, A.,Chevrier, B.,Barth, P.,Lamour, V.,Van Zandt, M.,Sibley, E.,Bon, C.,Moras, D.,Schneider, T.R.,Joachimiak, A.,Podjarny, A. (登録日: 2003-11-16, 公開日: 2004-05-07, 最終更新日: 2024-05-08)

主引用文献

Howard, E.I.,Sanishvili, R.,Cachau, R.E.,Mitschler, A.,Chevrier, B.,Barth, P.,Lamour, V.,Van Zandt, M.,Sibley, E.,Bon, C.,Moras, D.,Schneider, T.R.,Joachimiak, A.,Podjarny, A.
Ultrahigh Resolution Drug Design I: Details of Interactions in Human Aldose Reductase-Inhibitor Complex at 0.66 A.
Proteins, 55:792-, 2004

PubMed Abstract: The first subatomic resolution structure of a 36 kDa protein [aldose reductase (AR)] is presented. AR was cocrystallized at pH 5.0 with its cofactor NADP+ and inhibitor IDD 594, a therapeutic candidate for the treatment of diabetic complications. X-ray diffraction data were collected up to 0.62 A resolution and treated up to 0.66 A resolution. Anisotropic refinement followed by a blocked matrix inversion produced low standard deviations (<0.005 A). The model was very well ordered overall (CA atoms' mean B factor is 5.5 A2). The model and the electron-density maps revealed fine features, such as H-atoms, bond densities, and significant deviations from standard stereochemistry. Other features, such as networks of hydrogen bonds (H bonds), a large number of multiple conformations, and solvent structure were also better defined. Most of the atoms in the active site region were extremely well ordered (mean B approximately 3 A2), leading to the identification of the protonation states of the residues involved in catalysis. The electrostatic interactions of the inhibitor's charged carboxylate head with the catalytic residues and the charged coenzyme NADP+ explained the inhibitor's noncompetitive character. Furthermore, a short contact involving the IDD 594 bromine atom explained the selectivity profile of the inhibitor, important feature to avoid toxic effects. The presented structure and the details revealed are instrumental for better understanding of the inhibition mechanism of AR by IDD 594, and hence, for the rational drug design of future inhibitors. This work demonstrates the capabilities of subatomic resolution experiments and stimulates further developments of methods allowing the use of the full potential of these experiments.

PubMed: 15146478
DOI: 10.1002/PROT.20015

実験手法

X-RAY DIFFRACTION (0.66 Å)