ArticleThe Journal of biological chemistry2010
Hedgehog pathway antagonist 5E1 binds hedgehog at the pseudo-active site.
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 87 papers.
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Who cites it
87 citing papers in PubMed, 140 citations in OpenAlex.
- Liver-derived Indian hedgehog (Ihh) couples fast-feed transition to thermogenic and metabolic homeostasis.Molecular metabolism · 2026Article
- SHH Variant in a Father and a Son with Tracheobronchial Malformation.Molecular syndromology · 2026Article
- Catalysis of Native Chemical Ligation and Expressed Protein Ligation by Alkylselenols.JACS Au · 2025Article
- Injury-induced niche factors Cxcl12 and Shh/Ihh coordinate suture stem cell activation during calvarial bone regeneration.Science signaling · 2025Article
- Conserved C143 forms a branched intermediate in Hedgehog autoprocessing: A cancer drug discovery target against Hedgehog signaling.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Identification of small molecule antagonists of sonic hedgehog/heparin binding with activity in hedgehog functional assays.Biochimica et biophysica acta. General subjects · 2024Article
- Likelihood-based interactive local docking into cryo-EM maps in ChimeraX.Acta crystallographica. Section D, Structural biology · 2024Article
- Unravelling the Mysteries of the Sonic Hedgehog Pathway in Cancer Stem Cells: Activity, Crosstalk and Regulation.Current issues in molecular biology · 2024Review
- A Residual N-Terminal Peptide Enhances Signaling of Depalmitoylated Hedgehog to the Patched Receptor.Journal of developmental biology · 2024Article
- Current Status of Hedgehog Signaling Inhibitors.Current topics in medicinal chemistry · 2024Review
- Inactive metallopeptidase homologs: the secret lives of pseudopeptidases.Frontiers in molecular biosciences · 2024Review
- The ClusPro AbEMap web server for the prediction of antibody epitopes.Nature protocols · 2023Review
- The emerging roles of Hedgehog signaling in tumor immune microenvironment.Frontiers in oncology · 2023Review
- Molecular mechanisms underlying the action of carcinogens in gastric cancer with a glimpse into targeted therapy.Cellular oncology (Dordrecht, Netherlands) · 2022Review
- Higher Expressions of SHH and AR Are Associated with a Positive Receptor Status and Have Impact on Survival in a Cohort of Croatian Breast Cancer Patients.Life (Basel, Switzerland) · 2022Article
- Hedgehog Signaling Pathway Orchestrates Human Lung Branching Morphogenesis.International journal of molecular sciences · 2022Article
- Structural basis for catalyzed assembly of the Sonic hedgehog-Patched1 signaling complex.Developmental cell · 2022Article
- Hedgehog Autoprocessing: From Structural Mechanisms to Drug Discovery.Frontiers in molecular biosciences · 2022Review
- Molecular Mechanisms Involving the Sonic Hedgehog Pathway in Lung Cancer Therapy: Recent Advances.Frontiers in oncology · 2022Review
- Hedgehog-Interacting Protein is a multimodal antagonist of Hedgehog signalling.Nature communications · 2021Article
27 more citing papers are in PubMed but not listed here.
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Proper hedgehog (Hh) signaling is crucial for embryogenesis and tissue regeneration. Dysregulation of this pathway is associated with several types of cancer. The monoclonal antibody 5E1 is a Hh pathway inhibitor that has been extensively used to elucidate vertebrate Hh biology due to its ability to block binding of the three mammalian Hh homologs to the receptor, Patched1 (Ptc1). Here, we engineered a murine:human chimeric 5E1 (ch5E1) with similar Hh-binding properties to the original murine antibody. Using biochemical, biophysical, and x-ray crystallographic studies, we show that, like the regulatory receptors Cdon and Hedgehog-interacting protein (Hhip), ch5E1 binding to Sonic hedgehog (Shh) is enhanced by calcium ions. In the presence of calcium and zinc ions, the ch5E1 binding affinity increases 10-20-fold to tighter than 1 nm primarily because of a decrease in the dissociation rate. The co-crystal structure of Shh bound to the Fab fragment of ch5E1 reveals that 5E1 binds at the pseudo-active site groove of Shh with an epitope that largely overlaps with the binding site of its natural receptor antagonist Hhip. Unlike Hhip, the side chains of 5E1 do not directly coordinate the Zn(2+) cation in the pseudo-active site, despite the modest zinc-dependent increase in 5E1 affinity for Shh. Furthermore, to our knowledge, the ch5E1 Fab-Shh complex represents the first structure of an inhibitor antibody bound to a metalloprotease fold.
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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.