3K1O

Crystal structure of sterol 14-alpha demethylase (CYP51) from Trypanosoma cruzi in complex with a potential antichagasic drug, posaconazole

Summary for 3K1O

• Entry DOI: 10.2210/pdb3k1o/pdb
• Related: 3g1q 3i3k
• Descriptor: Sterol 14 alpha-demethylase, PROTOPORPHYRIN IX CONTAINING FE, 2,5-anhydro-1,3,4-trideoxy-2-(2,4-difluorophenyl)-6-O-{4-[4-(4-{1-[(1S,2S)-1-ethyl-2-hydroxypropyl]-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl}phenyl)piperazin-1-yl]phenyl}-1-(1H-1,2,4-triazol-1-yl)-D-erythro-hexitol, ... (4 entities in total)
• Functional Keywords: sterol 14-alpha demethylase, eburicol 14a-demethylase, cyp51, cytochrome p450, heme, oxidoreductase, monooxygenase, endoplasmic reticulum, transmembrane protein, sterol biosynthesis, lipids, membrane, iron, heme-thiolate protein
• Biological source: Trypanosoma cruzi
• Total number of polymer chains: 1
• Total formula weight: 53669.91

Authors

Lepesheva, G.I.,Hargrove, T.Y.,Anderson, S.,Wawrzak, Z.,Waterman, M.R. (deposition date: 2009-09-28, release date: 2009-10-27, Last modification date: 2023-09-06)

Primary citation

Lepesheva, G.I.,Hargrove, T.Y.,Anderson, S.,Kleshchenko, Y.,Furtak, V.,Wawrzak, Z.,Villalta, F.,Waterman, M.R.
Structural Insights into Inhibition of Sterol 14{alpha}-Demethylase in the Human Pathogen Trypanosoma cruzi.
J.Biol.Chem., 285:25582-25590, 2010

PubMed Abstract: Trypanosoma cruzi causes Chagas disease (American trypanosomiasis), which threatens the lives of millions of people and remains incurable in its chronic stage. The antifungal drug posaconazole that blocks sterol biosynthesis in the parasite is the only compound entering clinical trials for the chronic form of this infection. Crystal structures of the drug target enzyme, Trypanosoma cruzi sterol 14alpha-demethylase (CYP51), complexed with posaconazole, another antifungal agent fluconazole and an experimental inhibitor, (R)-4'-chloro-N-(1-(2,4-dichlorophenyl)-2-(1H-imid-azol-1-yl)ethyl)biphenyl-4-carboxamide (VNF), allow prediction of important chemical features that enhance the drug potencies. Combined with comparative analysis of inhibitor binding parameters, influence on the catalytic activity of the trypanosomal enzyme and its human counterpart, and their cellular effects at different stages of the Trypanosoma cruzi life cycle, the structural data provide a molecular background to CYP51 inhibition and azole resistance and enlighten the path for directed design of new, more potent and selective drugs to develop an efficient treatment for Chagas disease.

PubMed: 20530488
DOI: 10.1074/jbc.M110.133215

Experimental method

X-RAY DIFFRACTION (2.89 Å)