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| DOI | Trouver le DOI : https://doi.org/10.1038/s41598-021-83198-w |
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| Auteur | Rechercher : Sheff, Joey1; Rechercher : Wang, Ping1; Rechercher : Xu, Ping1; Rechercher : Arbour, Melanie1; Rechercher : Masson, Luke1; Rechercher : Van Faassen, Henk1; Rechercher : Hussack, Greg1; Rechercher : Kemmerich, Kristin1; Rechercher : Brunette, Eric1; Rechercher : Stanimirovic, Danica1; Rechercher : Hill, Jennifer J.1; Rechercher : Kelly, John1; Rechercher : Ni, Feng1 |
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| Affiliation | - Conseil national de recherches du Canada. Thérapeutique en santé humaine
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| Format | Texte, Article |
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| Sujet | biochemistry; drug discovery; structural biology |
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| Résumé | Ligand-activated signaling through the type 1 insulin-like growth factor receptor (IGF1R) is implicated in many physiological processes ranging from normal human growth to cancer proliferation and metastasis. IGF1R has also emerged as a target for receptor-mediated transcytosis, a transport phenomenon that can be exploited to shuttle biotherapeutics across the blood–brain barrier (BBB). We employed differential hydrogen–deuterium exchange mass spectrometry (HDX-MS) and nuclear magnetic resonance (NMR) to characterize the interactions of the IGF1R ectodomain with a recently discovered BBB-crossing single-domain antibody (sdAb), VHH-IR5, in comparison with IGF-1 binding. HDX-MS confirmed that IGF-1 induced global conformational shifts in the L1/FnIII-1/-2 domains and α-CT helix of IGF1R. In contrast, the VHH-IR5 sdAb-mediated changes in conformational dynamics were limited to the α-CT helix and its immediate vicinity (L1 domain). High-resolution NMR spectroscopy titration data and linear peptide scanning demonstrated that VHH-IR5 has high-affinity binding interactions with a peptide sequence around the C-terminal region of the α-CT helix. Taken together, these results define a core linear epitope for VHH-IR5 within the α-CT helix, overlapping the IGF-1 binding site, and suggest a potential role for the α-CT helix in sdAb-mediated transcytosis. |
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| Date de publication | 2021-02-19 |
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| Maison d’édition | Nature Research |
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| Licence | |
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| Dans | |
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| Langue | anglais |
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| Publications évaluées par des pairs | Oui |
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| Exporter la notice | Exporter en format RIS |
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| Signaler une correction | Signaler une correction (s'ouvre dans un nouvel onglet) |
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| Identificateur de l’enregistrement | e728127d-7bb4-4c3c-9f37-02ade41abddc |
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| Enregistrement créé | 2021-04-16 |
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| Enregistrement modifié | 2021-04-20 |
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