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Publication Abstract from PubMed

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 approximately 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.

A conformation-specific ON-switch for controlling CAR T cells with an orally available drug.,Zajc CU, Dobersberger M, Schaffner I, Mlynek G, Puhringer D, Salzer B, Djinovic-Carugo K, Steinberger P, De Sousa Linhares A, Yang NJ, Obinger C, Holter W, Traxlmayr MW, Lehner M Proc Natl Acad Sci U S A. 2020 Jun 30;117(26):14926-14935. doi:, 10.1073/pnas.1911154117. Epub 2020 Jun 17. PMID:32554495^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.