The structure of human recombinant aldose reductase complexed with the potent inhibitor zenarestat.
The crystal structure of the complex of human recombinant aldose reductase (AR) with zenarestat, one of its potent inhibitors, has been solved at 2.5 A resolution. Zenarestat fits neatly in the hydrophobic active site and induces unique and dramatic conformational changes. For example, the benzene ring of zenarestat occupies a gap in the side chains of Leu300 and Trp111 that interact directly and forms a CH-pi interaction in the native holoenzyme. As a result, the benzene ring of the inhibitor and these side chains form a CH-pi-pi interaction. Such structural information is key to understanding the mode of action of this class of inhibitors and for rational design of better therapeutics.
Kinoshita
Takayoshi
T
Exploratory Research Laboratories, Fujisawa Pharmaceutical Co. Ltd, 5-2-3, Tokodai, Tsukuba, Ibaraki 300-2698, Japan. takayoshi_kinoshita@po.fujisawa.co.jp
Miyake
Hiroshi
H
Fujii
Takashi
T
Takakura
Shoji
S
Goto
Toshio
T
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors / Q000737:chemistry*; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular; D011799:Quinazolines / Q000737:chemistry*; D011994:Recombinant Proteins / Q000737:chemistry
D004791:Enzyme Inhibitors; D011799:Quinazolines; D011994:Recombinant Proteins; C064920:FR 74366; D000449:Aldehyde Reductase