E3 ubiquitin-protein ligase (E3 ligase) (E3 ligase)

E3 ubiquitin-protein ligases are a diverse class of enzymes that catalyze the final step in the ubiquitination cascade, facilitating the transfer of ubiquitin from an E2 enzyme to a specific substrate protein [UniProt]. This process typically tags the substrate for degradation by the 26S proteasome, playing a critical role in maintaining protein homeostasis and regulating cell signaling pathways [PubMed]. In the field of targeted protein degradation (TPD), these enzymes are "recruited" by bifunctional molecules like PROTACs or molecular glues to induce the degradation of specific, often "undruggable," proteins of interest [Nature Reviews Drug Discovery]. While the human genome encodes over 600 E3 ligases, only a small subset, including Cereblon (CRBN) and Von Hippel-Lindau (VHL), are currently exploited for therapeutic recruitment [NIH]. Drugs that interact with these ligases, such as immunomodulatory imide drugs (IMiDs), have shown significant efficacy in treating hematologic malignancies by redirecting ligase activity toward neo-substrates [Wikipedia]. However, therapeutic challenges include the potential for off-target degradation, the "hook effect" in dosing, and the development of resistance through mutations in the ligase complex [Science].

Other names

Ubiquitin ligaseE3 enzymeProtein-ubiquitin ligaseRecruited E3 ligase

Recruitment of an E3 ubiquitin ligase to a target protein to induce proximity-based ubiquitination and proteasomal degradation [Nature Reviews Drug Discovery]; Inhibition of E3 ligase-substrate interaction [PubMed].