Figure 1. The structure and mechanism of PROTACs.

A) The general structure of a PROTAC molecule consists of a “warhead” ligand that recruits the protein of interest (POI), a linker, and an E3 ligand that recruits an E3 ubiquitin ligase. B) The “warhead” ligand and the E3 ligand bring into close proximity the protein of interest (POI) and an E3 ubiquitin ligase, respectively. The E3 ubiquitin ligase, in concert with an E2 ubiquitin-conjugating enzyme, promotes polyubiquitination of the POI. Polyubiquitination of the POI results in degradation by the 26S proteasome. This process is catalytic, meaning that the freed PROTAC molecule can participate in another reaction. Figure adapted from Pei et al. and Sun et al.^21,22