| Autor: |
Kretschmer S; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California 94158, United States.; California Quantitative Biosciences Institute (QBI) at UCSF, San Francisco, California 94158, United States., Perry N; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California 94158, United States.; California Quantitative Biosciences Institute (QBI) at UCSF, San Francisco, California 94158, United States.; University of California, Berkeley─University of California, San Francisco Joint Graduate Program in Bioengineering, San Francisco, California 94158, United States., Zhang Y; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California 94158, United States.; California Quantitative Biosciences Institute (QBI) at UCSF, San Francisco, California 94158, United States., Kortemme T; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California 94158, United States.; California Quantitative Biosciences Institute (QBI) at UCSF, San Francisco, California 94158, United States.; University of California, Berkeley─University of California, San Francisco Joint Graduate Program in Bioengineering, San Francisco, California 94158, United States. |
| Abstrakt: |
Protein-based switches that respond to different inputs to regulate cellular outputs, such as gene expression, are central to synthetic biology. For increased controllability, multi-input switches that integrate several cooperating and competing signals for the regulation of a shared output are of particular interest. The nuclear hormone receptor (NHR) superfamily offers promising starting points for engineering multi-input-controlled responses to clinically approved drugs. Starting from the VgEcR/RXR pair, we demonstrate that novel (multi)drug regulation can be achieved by exchange of the ecdysone receptor (EcR) ligand binding domain (LBD) for other human NHR-derived LBDs. For responses activated to saturation by an agonist for the first LBD, we show that outputs can be boosted by an agonist targeting the second LBD. In combination with an antagonist, output levels are tunable by up to three simultaneously present small-molecule drugs. Such high-level control validates NHRs as a versatile, engineerable platform for programming multidrug-controlled responses. |
