ArticleThe Journal of biological chemistry2010
Crystal structures of Trypanosoma brucei sterol 14alpha-demethylase and implications for selective treatment of human infections.
Article in The Journal of biological chemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 76 papers.
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Who cites it
76 citing papers in PubMed.
- TrypPROTACs Unlocking New Therapeutic Strategies for Chagas Disease.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Unique Structural Features Relate to Evolutionary Adaptation of Cytochrome P450 in the Abyssal Zone.International journal of molecular sciences · 2025Article
- CYP5122A1 encodes an essential sterol C4-methyl oxidase in Leishmania donovani and determines the antileishmanial activity of antifungal azoles.Nature communications · 2024Article
- Identification of Potent and Selective Inhibitors ofJournal of medicinal chemistry · 2024Article
- Druggable Sterol Metabolizing Enzymes in Infectious Diseases: Cell Targets to Therapeutic Leads.Biomolecules · 2024Review
- In Vitro and In Silico Evaluations of the Antileishmanial Activities of New Benzimidazole-Triazole Derivatives.Veterinary sciences · 2023Article
- Structural modeling of cytochrome P450 51 from a deep-sea fish points to a novel structural feature in other CYP51s.Journal of inorganic biochemistry · 2023Article
- Oxalactam A, a Novel Macrolactam with Potent Anti-Molecules (Basel, Switzerland) · 2022Article
- Unravelling the role of transient redox partner complexes in P450 electron transfer mechanics.Scientific reports · 2022Article
- Relaxed Substrate Requirements of Sterol 14α-Demethylase fromJournal of medicinal chemistry · 2021Article
- Concerning P450 Evolution: Structural Analyses Support Bacterial Origin of Sterol 14α-Demethylases.Molecular biology and evolution · 2021Article
- Synthesis, Docking, Computational Studies, and Antimicrobial Evaluations of New Dipeptide Derivatives Based on Nicotinoylglycylglycine Hydrazide.Molecules (Basel, Switzerland) · 2020Article
- Novel structural CYP51 mutation in Trypanosoma cruzi associated with multidrug resistance to CYP51 inhibitors and reduced infectivity.International journal for parasitology. Drugs and drug resistance · 2020Article
- Advances in preclinical approaches to Chagas disease drug discovery.Expert opinion on drug discovery · 2019Review
- Binding of a physiological substrate causes large-scale conformational reorganization in cytochrome P450 51.The Journal of biological chemistry · 2018Article
- Sterol 14α-Demethylase Structure-Based Optimization of Drug Candidates for Human Infections with the Protozoan Trypanosomatidae.Journal of medicinal chemistry · 2018Article
- CYP51 as drug targets for fungi and protozoan parasites: past, present and future.Parasitology · 2018Review
- Human cytochrome P450 enzymes 5-51 as targets of drugs and natural and environmental compounds: mechanisms, induction, and inhibition - toxic effects and benefits.Drug metabolism reviews · 2018Review
- Synthesis and Biological Activity of Sterol 14α-Demethylase and Sterol C24-Methyltransferase Inhibitors.Molecules (Basel, Switzerland) · 2018Review
- Sterol 14α-Demethylase Structure-Based Design of VNI (( R)- N-(1-(2,4-Dichlorophenyl)-2-(1 H-imidazol-1-yl)ethyl)-4-(5-phenyl-1,3,4-oxadiazol-2-yl)benzamide)) Derivatives To Target Fungal Infections: Synthesis, Biological Evaluation, and Crystallographic Analysis.Journal of medicinal chemistry · 2018Article
16 more citing papers are in PubMed but not listed here.
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12 authors.
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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.
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