Ubiquitin-protein ligase (E3 ligase) (E3 ligase)

Ubiquitin-protein ligases, or E3 ligases, are a diverse family of over 600 enzymes that serve as the critical substrate-recognition components of the ubiquitin-proteasome system (UPS) [UniProt, PubMed]. They facilitate the transfer of ubiquitin from an E2 conjugating enzyme to a specific target protein, marking it for degradation by the 26S proteasome or modulating its cellular function [NIH]. Dysregulation of E3 ligases is implicated in numerous diseases, particularly cancer, where they often over-degrade tumor suppressors like p53 or stabilize oncoproteins [PubMed, Frontiers]. In modern drug discovery, E3 ligases are targeted through two primary modalities: direct inhibition of their enzymatic activity and the use of bifunctional molecules like PROTACs or molecular glues [Nature Reviews Drug Discovery]. These proximity-inducing agents hijack the ligase to ubiquitinate and degrade previously "undruggable" proteins, such as transcription factors and scaffold proteins [ACS Central Science]. This class of targets is central to the field of targeted protein degradation, offering high specificity and the potential to overcome traditional resistance mechanisms [Guide to Pharmacology]. Clinical successes with cereblon-modulating drugs and emerging PROTACs like vepdegestrant highlight the therapeutic importance of this target class [Arvinas, PubMed].

Other names

E3 ubiquitin ligaseUbiquitin ligaseE3 enzymeUbiquitin-protein ligase complexCullin-RING ligaseHECT-type ligaseRING-type ligaseRBR-type ligase

E3 ligases function by facilitating the transfer of ubiquitin from an E2 conjugating enzyme to a substrate protein, typically leading to its degradation by the 26S proteasome [UniProt, PubMed]. Drugs target these components either by inhibiting their interaction with natural substrates (e.g., MDM2-p53 inhibitors) or by acting as molecular glues or PROTACs that recruit the E3 ligase to a neo-substrate for targeted degradation [Nature Reviews Drug Discovery, ACS Central Science].