Computational design of highly signalling-active membrane receptors through solvent-mediated allosteric networks.

ABSTRACT: Protein catalysis and allostery require the atomic-level orchestration and motion of residues and ligand, solvent and protein effector molecules. However, the ability to design protein activity through precise protein-solvent cooperative interactions has not yet been demonstrated. Here we report the design of 14 membrane receptors that catalyse G protein nucleotide exchange through diverse engineered allosteric pathways mediated by cooperative networks of intraprotein, protein-ligand and -solvent molecule interactions. Consistent with predictions, the designed protein activities correlated well with the level of plasticity of the networks at flexible transmembrane helical interfaces. Several designs displayed considerably enhanced thermostability and activity compared with related natural

SUBMITTER: Chen KM 

PROVIDER: S-EPMC11882447 | biostudies-literature | 2025 Mar

REPOSITORIES: biostudies-literature