![]() Typically, protein switches are triggered by a small molecule to control the assembly or disassembly of two protein subunits 1. In synthetic biology, many strategies have been pursued to control timing, localization, specificity and strength of transgene expression or signaling events by equipping cells with sophisticated genetic circuits governed by small-molecule controlled protein switches. ![]() Synthetic biology has enabled important developments on the understanding of fundamental aspects in biology as well as in next-generation cell-based therapies 1, 2, 3. ![]() This approach effectively expands the chemical space and logic responses in living cells and provides a blueprint to develop new ON- and OFF-switches. CDHs and AIRs showed excellent performance as drug responsive switches to control combinations of synthetic circuits in mammalian cells. To design ON-switches, we converted the CDHs into a multi-domain architecture which we refer to as activation by inhibitor release switches (AIR) that incorporate a rationally designed drug-insensitive receptor protein. The designed binders and drug-receptors form chemically-disruptable heterodimers (CDH) which dissociate in the presence of small molecules. ![]() Here, we present a computational protein design strategy to repurpose drug-inhibited protein-protein interactions as OFF- and ON-switches. However, the repertoire of small-molecule protein switches is insufficient for many applications, including those in the translational spaces, where properties such as safety, immunogenicity, drug half-life, and drug side-effects are critical. Small-molecule responsive protein switches are crucial components to control synthetic cellular activities. ![]()
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