Figure 1.

A. General structure of a PROTAC. The E3 ligase targeting “anchor” (blue) is connected to the specific POI targeting warhead (green) via a variable linker; B. mechanism of PROTAC-mediated target degradation via RING-type E3 ligases. (i) Ub transfer from E1 to E2 by trans-thioesterification is followed by complex formation with an E3 ligase; (ii) the PROTAC binds to both the E3 ligase and POI to form a TC, where the E3 ligase is shown as an assembly of scaffolding proteins (Sc), adapter proteins (Ad), and a SBD. This brings the E2 ligase into proximity to the POI; (iii) this leads to the transfer of multiple Ub units to surface exposed lysine residues; (iv) the resulting polyubiquitin chain is recognised by the proteasome, leading to the proteolytic degradation of the POI; and (v) the PROTAC is released and can catalyse the transfer of Ub to additional POIs