Recognition of substrate degrons by E3 ubiquitin ligases and modulation by small-molecule mimicry strategies

•E3 ligases recruit substrates for proteasomal degradation by recognition of degrons.•Crystal structures reveal the structural basis and mechanism of degron recognition.•Small-molecule degron mimetics can prevent or re-direct substrate recognition.•Small-molecule inducible degrons and PROTACs enable targeted protein degradation.

The ubiquitin-proteasome system is a master regulator of protein homeostasis, by which proteins are initially targeted for poly-ubiquitination by E3 ligases and then degraded into short peptides by the proteasome. Nature evolved diverse peptidic motifs, termed degrons, to signal substrates for degradation. We discuss degrons of the N-end rule pathway and also degrons characterized by post-translational modifications, including phosphorylation and hydroxylation. In each case we detail the structural basis of E3 ligase:degron recognition and small-molecule mimicry approaches that disrupt those protein-protein interactions. We present as well genetic and chemical technologies that enable targeted degradation of proteins of interest, namely small-molecule dependent inducible degrons and chemical degraders, for example, proteolysis-targeting chimeras (PROTACs).

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