Really Interesting New Gene E3 ubiquitin ligase (RING E3 ligase) (RING E3 ligase)

RING (Really Interesting New Gene) E3 ubiquitin ligases constitute the largest family of E3 ligases, defined by a characteristic zinc-binding domain that coordinates the transfer of ubiquitin from E2 enzymes to target proteins (UniProt, 2024). These enzymes are pivotal in maintaining cellular proteostasis by regulating the degradation of short-lived or misfolded proteins through the ubiquitin-proteasome system (Nature Reviews Molecular Cell Biology, 2009). In various pathologies, particularly oncology, RING E3 ligases like MDM2 and Cereblon (CRBN) are frequently exploited or dysregulated, making them high-value therapeutic targets (PubMed, 2020). Modern drug discovery utilizes these ligases as the catalytic engine for Targeted Protein Degradation (TPD), employing molecular glues and Proteolysis-Targeting Chimeras (PROTACs) to eliminate disease-causing proteins (Cell, 2017). This approach enables the targeting of proteins previously deemed "undruggable" by traditional small-molecule inhibitors. However, the broad biological impact of these ligases necessitates careful management of safety concerns, including potential teratogenicity and the development of drug resistance via ligase mutations (NIH, 2023).

Other names

RING finger E3 ubiquitin ligaseRING-type E3 ubiquitin transferaseReally Interesting New Gene finger proteinE3 ubiquitin-protein ligase (RING-type)

RING E3 ligases function as scaffolds that facilitate the transfer of ubiquitin from an E2 ubiquitin-conjugating enzyme directly to a substrate protein (Nature Reviews Molecular Cell Biology, 2009). Therapeutic agents like molecular glues (e.g., IMiDs) bind to the ligase to create a new interface for neo-substrates, while PROTACs act as heterobifunctional linkers that recruit the ligase to a specific protein of interest to trigger its proteasomal degradation (Cell, 2017).