Nanobody inhibitors of Plexin-B1 identify allostery in plexin–semaphorin interactions and signaling
Open accessAbstract
Plexin-B1 is a receptor for the cell surface semaphorin, Sema4D. This signaling system has been implicated in a variety of human diseases, including cancer, multiple sclerosis and osteoporosis. While inhibitors of the Plexin-B1:Sema4D interaction have been previously reported, understanding their mechanism has been hindered by an incomplete structural view of Plexin-B1. In this study, we have raised and characterized a pair of nanobodies that are specific for mouse Plexin-B1 and which inhibit the binding of Sema4D to mouse Plexin-B1 and its biological activity. Structural studies of these nanobodies reveal that they inhibit the binding of Sema4D in an allosteric manner, binding to epitopes not previously reported. In addition, we report the first unbound structure of human Plexin-B1, which reveals that Plexin-B1 undergoes a conformational change on Sema4D binding. These changes mirror those seen upon binding of allosteric peptide modulators, which suggests a new model for understanding Plexin-B1 signaling and provides a potential innovative route for therapeutic modulation of Plexin-B1.
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A nanobody blocking Plexin-B1 has recently been developed.
“In this context it is noteworthy that while small molecule inhibitors of plexin signaling are currently unavailable, a function-blocking antibody against Sema4D is being tested in a clinical trial for AD63, and a nanobody blocking Plexin-B1 has recently been developed64.”
From Regulation of cell distancing in peri-plaque glial nets by Plexin-B1 affects glial activation and amyloid compaction in Alzheimer’s disease (2024) · cites this paper as [64]
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“In this context, it is noteworthy that while small-molecule inhibitors of plexin signaling are currently unavailable, a function-blocking antibody against Sema4D is being tested in a clinical trial for AD 63 , and a nanobody blocking Plexin-B1 has recently been developed 64 .”
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- Authors
- Cowan, R., Trokter, M., Oleksy, A., Fedorova, M., Sawmynaden, K., Worzfeld, T., Offermanns, S., Matthews, D., Carr, M. D., & Hall, G.
- Affiliations
- University of Leicester (GB)
- LifeArc (GB)
- Philipps University of Marburg (DE)
- Max Planck Institute for Heart and Lung Research (DE)
- Corresponding author
- Hall, Gareth
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2023-06
- Volume
- 299
- Issue
- 6
- Pages
- 104740
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC10206189
- OpenAlex
- W4366779091
- Cited by
- 11
- References
- 44
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 4
- FWCI
- 1.33
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Figshare (submittedVersion, cc-by)
- Funders
- LifeArc
- European Synchrotron Radiation Facility
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Axon Guidance and Neuronal Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- Plexin-B1, Sema4D, nanobodies, allosteric inhibition, ligand-receptor interactions, conformational change, semaphorin signaling
- MeSH terms
- Animals, Nerve Tissue Proteins, Receptors, Cell Surface, Signal Transduction, Cell Adhesion Molecules, Semaphorins, Mice, Single-Domain Antibodies
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