Mechanistic insights into NET1–UNC5B complex formation and Its targeted disruption by NP137 fab and NET1 peptide competitors
Netrin‑1, a secreted protein initially characterized for its role in axon guidance, has emerged as a critical mediator of cancer progression. Preclinical studies with the anti‑netrin‑1 antibody NP137, which blocks the netrin‑1–UNC5B interaction, have demonstrated reactivation of tumor suppressor functions and sensitization of cancer cells to chemotherapy. Here, we identified the molecular binding interface of the netrin‑1–UNC5B complex using integrative structural and quantitative biophysical analyses. We then determined how NP137 binding inhibits this interaction by sterically blocking key contact points within the interface. Guided by these mechanistic insights, we rationally designed peptides that disrupt the netrin‑1–UNC5B complex through interfering with heparin-mediated stabilization of the complex by binding to shared heparin-binding sites. This comprehensive structural and mechanistic analysis advances understanding of netrin‑1 signaling and establishes strategies for therapeutic intervention in netrin‑1-driven malignancies. Netrin-1 signaling controls cell fate and is a key target in cancer research. Here, authors describe the structural basis of netrin-1–UNC5B signaling and study how antibody and peptide inhibitors disrupt this interaction
Authors
- Fabian Heide (ORCID: https://orcid.org/0000-0002-6849-3177)
- Candice Harder‐Viddal
- Ben A. Bailey-Elkin (ORCID: https://orcid.org/0000-0001-6863-2643)
- Oliver Peters (ORCID: https://orcid.org/0000-0001-8671-6955)
- John S. Klassen (ORCID: https://orcid.org/0000-0002-3389-7112)
- Elena N. Kitova (ORCID: https://orcid.org/0000-0003-0812-3286)
- Scott Legare (ORCID: https://orcid.org/0000-0003-4112-706X)
- Haben Gabir (ORCID: https://orcid.org/0000-0001-8775-6799)
- Monika Gupta (ORCID: https://orcid.org/0000-0003-4957-2918)
- Chiara Cabrele (ORCID: https://orcid.org/0000-0002-7550-6896)
- Patrick Mehlen (ORCID: https://orcid.org/0000-0003-1743-5417)
- Markus Meier (ORCID: https://orcid.org/0000-0003-1068-746X)
- Morgan Brisset (ORCID: https://orcid.org/0000-0002-4665-0661)
- Natalie Krahn (ORCID: https://orcid.org/0000-0003-0696-433X)
- Gay Pauline Padilla‐Meier (ORCID: https://orcid.org/0000-0003-1977-683X)
- Miguel Angel Alejandre Alcazar (ORCID: https://orcid.org/0000-0002-3176-0411)
- Manuel Koch (ORCID: https://orcid.org/0000-0002-2962-7814)
- Vesna Stanojlović (ORCID: https://orcid.org/0000-0001-5924-9634)
- Jörg Stetefeld (ORCID: https://orcid.org/0000-0003-1478-3248)
- Şerife Akgül (ORCID: https://orcid.org/0000-0003-0943-6241)
- Oleksiy Klymenko (ORCID: https://orcid.org/0000-0003-2156-6460)
- Faride Rafiei (ORCID: https://orcid.org/0000-0002-5314-4521)
- Abdelrhman Zakaria
- Roy Roshko
Institutions
- Université Claude Bernard Lyon 1 (FR)
- Centre National de la Recherche Scientifique (FR)
- University of Alberta (CA)
- Inserm (FR)
- University of Georgia (US)
- Public Health Agency of Canada (CA)
- University of Cologne (DE)
- University of Salzburg (AT)
- Hospital for Sick Children (CA)
- Netris Pharma (France) (FR)
- Centre de Recherche en Cancérologie de Lyon (FR)
- German Center for Lung Research (DE)
- Universities of Giessen and Marburg Lung Center (DE)
- University Hospital Cologne (DE)
- Max Planck Institute for Biology of Ageing (DE)
- Sickkids Research Institute (CA)
- University of Manitoba (CA)
- Canadian Mennonite University (CA)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-10-15
- DOI
- https://doi.org/10.1038/s41467-026-78641-3
- Primary Topic
- Cell death mechanisms and regulation
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Canadian Light Source
- Diamond Light Source
- Deutsche Forschungsgemeinschaft
- Canadian Institutes of Health Research