2026/01/31 by Erik Rihtar, Tina Fink, Filip Ivanovski +2 · 1 voice
Materials Science · Engineering · #Supramolecular Self-Assembly in Materials #Photochromic and Fluorescence Chemistry #Molecular Junctions and Nanostructures
paper · pdf · doi:10.1038/s41467-026-69099-4
openalex publication_date 2026/01/31 · openalex created_date 2026/02/02 · openalex updated_date 2026/08/01
Cells regulate processes through protein interaction networks. Most chemically induced dimerization (CID) systems respond to exogenous molecules, limiting integration with endogenous signaling. Here, we repurpose nuclear receptor (NR) ligand-binding domains (LBDs) and coactivators to develop hormone- or clinically approved drug-responsive CIDs. Using the LBDs of TRβ, VDR, RARγ, ERβ, and GR2 with a TIF2 coactivator peptide, we constructed CIDs responsive to triiodothyronine, vitamin D, retinoic acid, estrogen, cortisol, and their antagonists. These CIDs enable two-input transcriptional switches for gene regulation. Furthermore, we design hormone-responsive liquid-liquid phase-separated (LLPS) condensates that strongly amplify transcription when exceeding a critical interaction threshold. These functional LLPS condensates provide a tunable platform for transcriptional control with up to several hundred-fold activation. Our findings offer an approach for integrating synthetic biology with physiological signaling, advancing applications in gene circuits, biosensing, and therapeutics through ligand-controlled LLPS formation. Two-input chemogenetic tools remain limited. Here, authors develop ligand-responsive systems based on human nuclear receptors, using agonists and antagonists to reversibly control protein interactions and cellular processes, including synthetic protein condensate formation to enhance transcription.