Function-focused protein design

Abstract

Protein Design De novo design allows the creation of new types of stable folds in proteins; however, building in successful function remains challenging. Yang et al. describe a bottom-up approach in which they conceived structures around functional motifs and then used targeted screening to optimize their composition. Based on thousands of blueprints, they screened yeast libraries in which most residues were restricted to those found most frequently in the designs, but critical core residues were allowed limited variability constrained by these designs. This approach enabled the authors to discover five folds that accommodated four different binding motifs, including a protein that displays two motifs. They then built proteins that are functional as biosensors of specific antibody epitopes and others that act as ligands to regulate synthetic receptors in mammalian cells. Nat. Chem. Biol. 10.1038/s41589-020-00699-x (2020).