title: The structure of human recombinant aldose reductase complexed with the potent inhibitor zenarestat.
abstract: 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.
authors.affiliation: Exploratory Research Laboratories, Fujisawa Pharmaceutical Co. Ltd, 5-2-3, Tokodai, Tsukuba, Ibaraki 300-2698, Japan. takayoshi_kinoshita@po.fujisawa.co.jp
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Kinoshita
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Miyake
authors.forename: Takashi
authors.initials: T
authors.lastname: Fujii
authors.forename: Shoji
authors.initials: S
authors.lastname: Takakura
authors.forename: Toshio
authors.initials: T
authors.lastname: Goto
mesh_terms: 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
chemical_list: D004791:Enzyme Inhibitors; D011799:Quinazolines; D011994:Recombinant Proteins; C064920:FR 74366; D000449:Aldehyde Reductase