3GW9

Crystal structure of sterol 14-alpha demethylase (CYP51) from Trypanosoma brucei bound to an inhibitor N-(1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethyl)-4-(5-phenyl-1,3,4-oxaziazol-2-yl)benzamide

3GW9 の概要

• エントリーDOI: 10.2210/pdb3gw9/pdb
• 関連するPDBエントリー: 3G1Q
• 分子名称: STEROL 14ALPHA-DEMETHYLASE, PROTOPORPHYRIN IX CONTAINING FE, N-[(1R)-1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethyl]-4-(5-phenyl-1,3,4-oxadiazol-2-yl)benzamide, ... (4 entities in total)
• 機能のキーワード: sterol 14alpha-demethylase, cyp51, cytochrome p450, heme, oxidoreductase, monooxygenase, sterol biosynthesis, lipids, endoplasmic reticulum, iron, heme-thiolate protein
• 由来する生物種: Trypanosoma brucei
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 208556.45

構造登録者

Lepesheva, G.I.,Hargrove, T.Y.,Harp, J.,Wawrzak, Z.,Waterman, M.R. (登録日: 2009-03-31, 公開日: 2009-11-17, 最終更新日: 2023-09-06)

主引用文献

Lepesheva, G.I.,Park, H.W.,Hargrove, T.Y.,Vanhollebeke, B.,Wawrzak, Z.,Harp, J.M.,Sundaramoorthy, M.,Nes, W.D.,Pays, E.,Chaudhuri, M.,Villalta, F.,Waterman, M.R.
Crystal structures of Trypanosoma brucei sterol 14alpha-demethylase and implications for selective treatment of human infections.
J.Biol.Chem., 285:1773-1780, 2010

PubMed Abstract: Sterol 14alpha-demethylase (14DM, the CYP51 family of cytochrome P450) is an essential enzyme in sterol biosynthesis in eukaryotes. It serves as a major drug target for fungal diseases and can potentially become a target for treatment of human infections with protozoa. Here we present 1.9 A resolution crystal structures of 14DM from the protozoan pathogen Trypanosoma brucei, ligand-free and complexed with a strong chemically selected inhibitor N-1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethyl)-4-(5-phenyl-1,3,4-oxadi-azol-2-yl)benzamide that we previously found to produce potent antiparasitic effects in Trypanosomatidae. This is the first structure of a eukaryotic microsomal 14DM that acts on sterol biosynthesis, and it differs profoundly from that of the water-soluble CYP51 family member from Mycobacterium tuberculosis, both in organization of the active site cavity and in the substrate access channel location. Inhibitor binding does not cause large scale conformational rearrangements, yet induces unanticipated local alterations in the active site, including formation of a hydrogen bond network that connects, via the inhibitor amide group fragment, two remote functionally essential protein segments and alters the heme environment. The inhibitor binding mode provides a possible explanation for both its functionally irreversible effect on the enzyme activity and its selectivity toward the 14DM from human pathogens versus the human 14DM ortholog. The structures shed new light on 14DM functional conservation and open an excellent opportunity for directed design of novel antiparasitic drugs.

PubMed: 19923211
DOI: 10.1074/jbc.M109.067470

実験手法

X-RAY DIFFRACTION (1.87 Å)