The protein backbones of these new structures are essentially superimposable with that of the background GNCA4-WT variant (Figure ) and, therefore, the observed enhancement of catalysis is likely linked to small re-arrangements in the de novo active site (Figure ). ), with a transition state analogue bound in the active site. Note that we have changed the orientation of the active site compared to panel (A), to better highlight the changes in key active site side chains.