Sense and respond Many signaling pathways start with cellular proteins sensing and responding to small molecules. Despite advances in protein design, creating a protein-based sense-and-respond system remains challenging. Glasgow et al. designed binding sites at the interface of protein heterodimers (see the Perspective by Chica). By fusing each monomer to one half of a split reporter, they linked ligand-driven dimerization to the reporter output. The computational design strategy provides a generalizable approach to create synthetic sensing systems with different outputs. Science , this issue p. 1024 ; see also p. 952