ArticleProceedings of the National Academy of Sciences of the United States of America2008
Crystal structures of substrate-bound and substrate-free cytochrome P450 46A1, the principal cholesterol hydroxylase in the brain.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT03706885 (A Proof-of-Concept Clinical Research Study of Efavirenz in Patients With Alzheimer's Disease), which is not on this map. Cited by 61 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
A Proof-of-Concept Clinical Research Study of Efavirenz in Patients With Alzheimer's Disease
Who cites it
61 citing papers in PubMed, 137 citations in OpenAlex.
- CYP46A1-Targeted Treatment Alleviates Long-Term White Matter Injury Following Traumatic Brain Injury by Promoting Cholesterol Metabolic Clearance and Remyelination.CNS neuroscience & therapeutics · 2026Article
- Interactions of Linalool and Linalyl Acetate with Selected Dog Cytochrome P450 (CYP) Proteins Identified by In Silico Drug Discovery Followed by Molecular Docking Analysis.Pharmaceuticals (Basel, Switzerland) · 2025Article
- Treatment with efavirenz extends survival in a Creutzfeldt-Jakob disease model by regulating brain cholesterol metabolism.JCI insight · 2025Article
- Molecular dynamics, docking and quantum calculations reveal conformational changes influenced by CYP271A amino acid mutations related to cerebrotendinous xanthomatosis.Scientific reports · 2025Article
- Brain cholesterol and Alzheimer's disease: challenges and opportunities in probe and drug development.Brain : a journal of neurology · 2024Review
- Assessment of cholesterol homeostasis in the living human brain.Science translational medicine · 2022Article
- The Hydroxylation Position Rather than Chirality Determines How Efavirenz Metabolites Activate Cytochrome P450 46A1 In Vitro.Drug metabolism and disposition: the biological fate of chemicals · 2022Article
- Brain Cholesterol Biosynthetic Pathway Is Altered in a Preclinical Model of Fragile X Syndrome.International journal of molecular sciences · 2022Article
- Identification of potential inhibitors of brain-specific CYP46A1 from phytoconstituents in Indian traditional medicinal plants.Journal of proteins and proteomics · 2022Article
- Oral administration of repurposed drug targeting Cyp46A1 increases survival times of prion infected mice.Acta neuropathologica communications · 2021Article
- Cholesterol Hydroxylating Cytochrome P450 46A1: From Mechanisms of Action to Clinical Applications.Frontiers in aging neuroscience · 2021Review
- Dynamics and Mechanism of Binding of Androstenedione to Membrane-Associated Aromatase.Biochemistry · 2020Article
- In Vitro Activation of Cytochrome P450 46A1 (CYP46A1) by Efavirenz-Related Compounds.Journal of medicinal chemistry · 2020Article
- Synthesis and pharmacokinetic study of aBioorganic & medicinal chemistry letters · 2020Article
- Therapeutic implications of altered cholesterol homeostasis mediated by loss of CYP46A1 in human glioblastoma.EMBO molecular medicine · 2020Article
- Cholesterol 24-Hydroxylation by CYP46A1: Benefits of Modulation for Brain Diseases.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2019Review
- Conformational selection dominates binding of steroids to human cytochrome P450 17A1.The Journal of biological chemistry · 2019Article
- Structural variation during dog domestication: insights from gray wolf and dhole genomes.National science review · 2019Article
- Binding of a physiological substrate causes large-scale conformational reorganization in cytochrome P450 51.The Journal of biological chemistry · 2018Article
- 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
1 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 2 countries.
Funding
Abstract
By converting cholesterol to 24S-hydroxycholesterol, cytochrome P450 46A1 (CYP46A1) initiates the major pathway for cholesterol removal from the brain. Two crystal structures of CYP46A1 were determined. First is the 1.9-A structure of CYP46A1 complexed with a high-affinity substrate cholesterol 3-sulfate (CH-3S). The second structure is that of the substrate-free CYP46A1 at 2.4-A resolution. CH-3S is bound in the productive orientation and occupies the entire length of the banana-shaped hydrophobic active-site cavity. A unique helix B'-C loop insertion (residues 116-120) contributes to positioning cholesterol for oxygenation catalyzed by CYP46A1. A comparison with the substrate-free structure reveals substantial substrate-induced conformational changes in CYP46A1 and suggests that structurally distinct compounds could bind in the enzyme active site. In vitro assays were performed to characterize the effect of different therapeutic agents on cholesterol hydroxylase activity of purified full-length recombinant CYP46A1, and several strong inhibitors and modest coactivators of CYP46A1 were identified. Structural and biochemical data provide evidence that CYP46A1 activity could be altered by exposure to some therapeutic drugs and potentially other xenobiotics.
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