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Gewählte Publikation:

Zajc, CU; Dobersberger, M; Schaffner, I; Mlynek, G; Puhringer, D; Salzer, B; Djinovic-Carugo, K; Steinberger, P; Linhares, AD; Yang, NJ; Obinger, C; Holter, W; Traxlmayr, MW; Lehner, M.
(2020): A conformation-specific ON-switch for controlling CAR T cells with an orally available drug
P NATL ACAD SCI USA. 2020; 117(26): 14926-14935. FullText FullText_BOKU

Molecular ON-switches in which a chemical compound induces protein-protein interactions can allow cellular function to be controlled with small molecules. ON-switches based on clinically applicable compounds and human proteins would greatly facilitate their therapeutic use. Here, we developed an ON-switch system in which the human retinol binding protein 4 (hRBP4) of the lipocalin family interacts with engineered hRBP4 binders in a small molecule-dependent manner. Two different protein scaffolds were engineered to bind to hRBP4 when loaded with the orally available small molecule A1120. The crystal structure of an assembled ON-switch shows that the engineered binder specifically recognizes the conformational changes induced by A1120 in two loop regions of hRBP4. We demonstrate that this conformation-specific ON-switch is highly dependent on the presence of A1120, as demonstrated by an similar to 500-fold increase in affinity upon addition of the small molecule drug. Furthermore, the ON-switch successfully regulated the activity of primary human CAR T cells in vitro. We anticipate that lipocalin-based ON-switches have the potential to be broadly applied for the safe pharmacological control of cellular therapeutics.
Autor/innen der BOKU Wien:
Obinger Christian
Schaffner Irene
Traxlmayr Michael
Zajc Charlotte
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Find related publications in this database (Keywords)
protein engineering
CAR T cell
alternative scaffold

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