Nature·· 9 hours agoPickScore84
De novo design of cysteine proteases.
In brief
A Nature study reports the de novo design of cysteine proteases, with 13/69 designs active, a 19% success rate, and catalytic rate enhancements of up to 3×10⁷. Six crystal structures match the design models with Cα RMSD <1.2 Å, and the folds differ greatly from natural proteases (TM score <0.50). The work identifies imperfect active-site preorganization and substrate positioning as the main sources of the activity gap, and shows the designed enzymes efficiently cleave target substrates in mammalian cells (DOI 10.1038/s41586-026-11143-w).
Why it matters
The study achieves de novo enzyme design for high-energy-barrier peptide bond hydrolysis, with 19% success and crystal structures validating the method's generality.
Source: Nature