Figure 1.

A schematic overview of cullin-RING E3 ligase (CRL) and NEDD8 conjugation. Conjugation of NEDD8 to the scaffold cullin protein in the CRL is carried out in three enzymatic steps involving NEDD8-activating enzyme (NAE, E1^N), UBC12, and UBE2F (E2^N). The substrate receptor protein, docked in the CRL complex by binding to the adaptor protein, recruits substrates for ubiquitin conjugation. MLN4924 and TAS4464 are specific NAE inhibitors, prohibiting NEDD8 conjugation and thus inhibit CRL activity. The 2-D structure of MLN4924 and TAS4464 was derived from Yu et al. (34). N, NEDD8; U, ubiquitin; Rbx, RING box protein.