ArticleNature communications2020
Structural basis for itraconazole-mediated NPC1 inhibition.
Article in Nature communications, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
What it found
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Who cites it
45 citing papers in PubMed, 73 citations in OpenAlex.
- From fungus fighter to cancer slayer: itraconazole as a multifaceted candidate for drug-resistant prostate cancer.Prostate cancer and prostatic diseases · 2026Review
- Article
- Replacing Antibiotics with Synergistic Probiotics-Microalgae Consortium in Mud Crab (Antibiotics (Basel, Switzerland) · 2026Article
- A Phase I Study of Hydroxychloroquine and Suba-Itraconazole in Men with Biochemical Relapse of Prostate Cancer (HITMAN-PC): Dose Escalation Results.Cancer research communications · 2026Article
- Review
- NPC1 as a novel therapeutic target for induction of pyroptosis in cancers.Biomarker research · 2025Article
- Computational Elucidation of Sterol Recognition by SREBP Cleavage Activatory Protein.Journal of chemical information and modeling · 2025Article
- Molecular insights into human phosphatidylserine synthase 2 and its regulation of SREBP pathways.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Inhibiting hedgehog signal by a patched-1 antibody.Cell discovery · 2025Article
- Inhibition of OSBP blocks retrograde trafficking by inducing partial Golgi degradation.Nature chemical biology · 2025Article
- Structural and biochemical analysis of ligand binding in yeast Niemann-Pick type C1-related protein.Life science alliance · 2025Article
- Mutant induced neurons and humanized mice enable identification of Niemann-Pick type C1 proteostatic therapies.JCI insight · 2024Article
- Conformational changes in the Niemann-Pick type C1 protein NCR1 drive sterol translocation.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Glycosphingolipids are linked to elevated neurotransmission and neurodegeneration in a Drosophila model of Niemann Pick type C.Disease models & mechanisms · 2023Article
- MicroRNA Profile, Putative Diagnostic Biomarkers and RNA-Based Therapies in the Inherited Lipid Storage Disease Niemann-Pick Type C.Biomedicines · 2023Review
- Cellular and molecular mechanisms of Hedgehog signalling.Nature reviews. Molecular cell biology · 2023Review
- The energetics and ion coupling of cholesterol transport through Patched1.Science advances · 2023Article
- Lysosome-targeted multifunctional lipid probes reveal the sterol transporter NPC1 as a sphingosine interactor.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- The Energetics and Ion Coupling of Cholesterol Transport Through Patched1.bioRxiv : the preprint server for biology · 2023Article
- The Cerebellum in Niemann-Pick C1 Disease: Mouse Versus Man.Cerebellum (London, England) · 2023Review
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
Niemann-Pick C1 (NPC1), a lysosomal protein of 13 transmembrane helices (TMs) and three lumenal domains, exports low-density-lipoprotein (LDL)-derived cholesterol from lysosomes. TMs 3-7 of NPC1 comprise the Sterol-Sensing Domain (SSD). Previous studies suggest that mutation of the NPC1-SSD or the addition of the anti-fungal drug itraconazole abolishes NPC1 activity in cells. However, the itraconazole binding site and the mechanism of NPC1-mediated cholesterol transport remain unknown. Here, we report a cryo-EM structure of human NPC1 bound to itraconazole, which reveals how this binding site in the center of NPC1 blocks a putative lumenal tunnel linked to the SSD. Functional assays confirm that blocking this tunnel abolishes NPC1-mediated cholesterol egress. Intriguingly, the palmitate anchor of Hedgehog occupies a similar site in the homologous tunnel of Patched, suggesting a conserved mechanism for sterol transport in this family of proteins and establishing a central function of their SSDs.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.