Crystal structures of Trypanosoma brucei sterol 14alpha-demethylase and implications for selective treatment of human infections
| العنوان: | Crystal structures of Trypanosoma brucei sterol 14alpha-demethylase and implications for selective treatment of human infections |
|---|---|
| المؤلفون: | Munirathinam Sundaramoorthy, Etienne Pays, Michael R. Waterman, W. David Nes, Benoit Vanhollebeke, Joel M. Harp, Hee Won Park, Minu Chaudhuri, Tatiana Y. Hargrove, Fernando Villalta, Zdzislaw Wawrzak, Galina I. Lepesheva |
| المصدر: | The Journal of biological chemistry, 285 (3 |
| سنة النشر: | 2010 |
| مصطلحات موضوعية: | Models, Molecular, Protein Conformation, Trypanocidal Agents -- therapeutic use, Enzyme Inhibitors -- metabolism, Crystallography, X-Ray, Ligands, Biochemistry, Substrate Specificity, Sterol 14-Demethylase, Protein structure, Cytochrome P-450 Enzyme System, Enzyme Inhibitors -- pharmacology, Cytochrome P-450 Enzyme Inhibitors, Benzamides -- pharmacology, Enzyme Inhibitors -- therapeutic use, Trypanocidal Agents -- chemistry, Trypanosoma brucei brucei -- drug effects, Trypanosoma brucei brucei -- enzymology, Enzyme Inhibitors, Benzamides -- metabolism, Cytochrome P-450 Enzyme System -- metabolism, biology, Sciences bio-médicales et agricoles, Trypanosomiasis, African -- drug therapy, Trypanocidal Agents, Sterols, Protein Structure and Folding, Benzamides, Trypanocidal Agents -- metabolism, Antiparasitic, medicine.drug_class, Trypanosoma brucei brucei, Trypanosoma brucei, Benzamides -- therapeutic use, Trypanocidal Agents -- pharmacology, Enzyme activator, Enzyme Inhibitors -- chemistry, Microsomes, medicine, Humans, Amino Acid Sequence, Molecular Biology, Benzamides -- chemistry, Active site, Cell Biology, biology.organism_classification, Sterol, Microsomes -- enzymology, Trypanosomiasis, African, Cytochrome P-450 Enzyme System -- chemistry, Drug Design, Sterols -- biosynthesis, biology.protein, Biocatalysis, Cytochrome P-450 Enzyme System -- antagonists & inhibitors |
| الوصف: | 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. Journal Article Research Support, N.I.H. Extramural Research Support, Non-U.S. Gov't SCOPUS: ar.j info:eu-repo/semantics/published |
| وصف الملف: | 2 full-text file(s): application/pdf; application/pdf |
| اللغة: | English |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a10f25cf6d7a799ccbb98ab7ab7cd026 http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/51605 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....a10f25cf6d7a799ccbb98ab7ab7cd026 |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |