ArticleProceedings of the National Academy of Sciences of the United States of America2020
Hedgehog pathway activation through nanobody-mediated conformational blockade of the Patched sterol conduit.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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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.
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Who cites it
23 citing papers in PubMed.
- Mechanistic trade-offs between local and long-range signaling activity in natural and synthetic morphogens.Science advances · 2026Article
- Article
- Engineered mucus-tethering bispecific nanobodies enhance mucosal immunity against respiratory pathogens.Nature nanotechnology · 2026Article
- Development of an allosteric adhesion GPCR nanobody with therapeutic potential.Nature chemical biology · 2025Article
- 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
- 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
- The Inseparable Relationship Between Cholesterol and Hedgehog Signaling.Annual review of biochemistry · 2023Review
- The Energetics and Ion Coupling of Cholesterol Transport Through Patched1.bioRxiv : the preprint server for biology · 2023Article
- Membranes under the Magnetic Lens: A Dive into the Diverse World of Membrane Protein Structures Using Cryo-EM.Chemical reviews · 2022Review
- The sense of taste: Development, regeneration, and dysfunction.WIREs mechanisms of disease · 2022Review
- 3D reconstruction from cryo-EM projection images using two spherical embeddings.Communications biology · 2022Article
- Structural basis for catalyzed assembly of the Sonic hedgehog-Patched1 signaling complex.Developmental cell · 2022Article
- Conserved cholesterol-related activities of Dispatched 1 drive Sonic hedgehog shedding from the cell membrane.Journal of cell science · 2022Article
- Sterol regulation of developmental and oncogenic Hedgehog signaling.Biochemical pharmacology · 2022Review
- Neurosensory development of the four brainstem-projecting sensory systems and their integration in the telencephalon.Frontiers in neural circuits · 2022Article
- Dispatched uses NaNature · 2021Article
- Dispatching plasma membrane cholesterol and Sonic Hedgehog dispatch: two sides of the same coin?Biochemical Society transactions · 2021Review
- Article
- A Small Virus to Deliver Small Antibodies: New Targeted Therapies Based on AAV Delivery of Nanobodies.Microorganisms · 2021Review
Corrections and comments
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Authors and funding
12 authors.
Funding
Abstract
Activation of the Hedgehog pathway may have therapeutic value for improved bone healing, taste receptor cell regeneration, and alleviation of colitis or other conditions. Systemic pathway activation, however, may be detrimental, and agents amenable to tissue targeting for therapeutic application have been lacking. We have developed an agonist, a conformation-specific nanobody against the Hedgehog receptor Patched1 (PTCH1). This nanobody potently activates the Hedgehog pathway in vitro and in vivo by stabilizing an alternative conformation of a Patched1 "switch helix," as revealed by our cryogenic electron microscopy structure. Nanobody-binding likely traps Patched in one stage of its transport cycle, thus preventing substrate movement through the Patched1 sterol conduit. Unlike the native Hedgehog ligand, this nanobody does not require lipid modifications for its activity, facilitating mechanistic studies of Hedgehog pathway activation and the engineering of pathway activating agents for therapeutic use. Our conformation-selective nanobody approach may be generally applicable to the study of other PTCH1 homologs.
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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.