Fig. 1
From: PROTAC’ing oncoproteins: targeted protein degradation for cancer therapy
PROTACs induce catalytic proteasomal degradation of their targets. PROTACs are heterobifunctional compounds comprised of a ligand for a target protein and a ligand for an E3 ligase joined by a linker. Simultaneous binding of a target protein and an E3 ligase promotes the formation of ternary complexes: Target-PROTAC-E3 Ligase. E3 ligases serve as adaptor proteins for E2 ligases by conferring selective target recruitment. E2 ligases receive activated ubiquitin tags from E1 ligase and conjugate ubiquitin to surface lysine residues of the target protein. Ubiquitin tags may also be ligated to pre-existing ubiquitin tags to form polyubiquitin chains. Ternary complexes may dissociate after target ubiquitylation to enable iterative target degradation by a single PROTAC molecule. Polyubiquitylated targets are recognized by the 26S proteosome where they are degraded. Image created in Biorender and Chemdraw