Constrained TACC3 peptidomimetics for a non-canonical protein-protein interface elucidate allosteric communication in Aurora-A kinase.

ABSTRACT: Peptidomimetic design for non-canonical interfaces is less well established than for α-helix and β-strand mediated protein-protein interactions. Using the TACC3/Aurora-A kinase interaction as a model, we developed a series of constrained TACC3 peptide variants with 10-fold increased binding potencies (K _d) towards Aurora-A in comparison to the parent peptide. High-affinity is achieved in part by restricting the accessible conformational ensemble of the peptide leading to a more favourable entropy of binding. In addition to acting as potent orthosteric TACC3/Aurora-A inhibitors, these peptidomimetics were shown to activate the kinase and inhibit the N-Myc/Aurora-A interaction at a distal site. Thus, the potency of these tools uniquely allowed us to unveil new insight into

SUBMITTER: Gimenez D 

PROVIDER: S-EPMC11604048 | biostudies-literature | 2024 Dec

REPOSITORIES: biostudies-literature