Fig. 1: Canonical neddylation pathway.
From: Discovery of neddylation E2s inhibitors with therapeutic activity
Precursor NEDD8 with hydrolase is the first process before NEDD8 reacts with NAE. By actions of ATP and Mg2+, NAE is first loaded with one NEDD8 molecule. Following the same procedure, the second NEDD8 is attached with NAE. Double NEDD8 loaded NAE allows conjugating enzyme E2 binding and transferring NEDD8 from NAE’s active cysteine to E2’s cysteine. Next, by coordinating with E3 ligase, NEDD8 moves to the target protein. Finally, through the deneddylation process, NEDD8 is removed from the substrates.
