<i>De Novo</i>-Designed APC/C Inhibitors Provide a Rationale for Targeting RING-Type E3 Ubiquitin Ligases.

ABSTRACT: The ubiquitin system represents an attractive pharmacological target for numerous pathological processes, including cancer and neurodegeneration. RING domain-containing E3 ubiquitin ligases constitute the largest class of ubiquitin enzymes, providing a scaffold for substrate recognition and catalysis. Their shallow groove recognition interfaces involving discontinuous epitopes and a lack of defined binding pockets have largely rendered them undruggable. Inspired by natural RING inhibitors, we have developed a pharmacophore-based strategy for the rational design of peptidomimetics targeting RING domains, and we demonstrate its feasibility by using the macromolecular APC/C complex (anaphase-promoting complex/cyclosome). We designed scaffolds binding to the APC/C RING domain and efficiently i

SUBMITTER: Ruiz-Gomez G 

PROVIDER: S-EPMC12169662 | biostudies-literature | 2025 Jun

REPOSITORIES: biostudies-literature