Computational remodeling of an enzyme conformational landscape for altered substrate selectivity.

ABSTRACT: Structural plasticity of enzymes dictates their function. Yet, our ability to rationally remodel enzyme conformational landscapes to tailor catalytic properties remains limited. Here, we report a computational procedure for tuning conformational landscapes that is based on multistate design of hinge-mediated domain motions. Using this method, we redesign the conformational landscape of a natural aminotransferase to preferentially stabilize a less populated but reactive conformation and thereby increase catalytic efficiency with a non-native substrate, resulting in altered substrate selectivity. Steady-state kinetics of designed variants reveals activity increases with the non-native substrate of approximately 100-fold and selectivity switches of up to 1900-fold. Structural analyses by room

SUBMITTER: St-Jacques AD 

PROVIDER: S-EPMC10539519 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature