Fig. 1. (A) PROTAC mechanism. (1) PROTACs engage their binding partners forming a ternary complex (2) stabilized by de novo protein–protein interactions. (3) The POI is then ubiquitinated by the E3 ligase, resulting in proteasomal degradation of the POI (4). (5) Noncovalent PROTACs can dissociate from the ternary complex and induce multiple cycles of degradation. (B) PROTACs that covalently bind the E3 ligase, but reversibly bind the POI can also undergo catalytic rounds of degradation. (C) PROTACs that covalently bind the POI cannot participate in catalytic rounds of degradation. PROTACs that bind in a covalent, reversible manner to either the E3 ligase or POI would have the catalytic cycle shown in A.