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Targeted protein degradation

You can glue it too!

Nature Chemical Biology volume 13, pages 452–453 (2017)Cite this article

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Proteolysis-targeting chimera (PROTACs) are synthetic molecules that recruit neo-substrate proteins to a ubiquitin ligase for ubiquitination and subsequent degradation. Structural insight into the VHL–MZ1–BRD4 complex reveals how the rationally designed MZ1–PROTAC molecule mediates degradation of an unnatural protein substrate.

The physiological role of the majority of E3 ubiquitin ligases is to ubiquitinate native substrate proteins, targeting them for proteolysis by the 26S proteasome. The cullin–RING ligase (CRL) family comprises over 230 different CRLs that recognize hundreds of substrates throughout diverse cellular pathways8. Substrate recruitment depends on short peptide sequences, called destruction motifs, or degrons, and is regulated by post-translational modifications, protein cofactors, or low-molecular-weight compounds. Fusion of degrons to unrelated proteins results in degradation, illustrating that ubiquitination is highly promiscuous and restrained mostly by spatial proximity to the ligase9. Thalidomide, clinically used in the treatment of multiple myeloma, emerged as the first synthetic small molecule that takes advantage of an E3 ligase10. Thalidomide repurposes the CRL4CRBN (cereblon) ubiquitin ligase by acting as molecular glue that mounts disease-related proteins onto the E3 ligase9. The glue-induced protein–protein interactions substantially contribute to target specificity (Fig. 1b). The coincidental discovery of thalidomide's mode of action provided precedence for a novel class of drugs and revived efforts to artificially induce degradation of key therapeutic targets by synthetic molecules.

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Figure 1: Mechanism of neo-substrate degradation by bifunctional degraders.

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Authors and Affiliations

  1. Michal J. Walczak, Georg Petzold and Nicolas H. Thomä are at the Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.,

    Michal J Walczak, Georg Petzold & Nicolas H Thomä

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  1. Michal J Walczak
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  2. Georg Petzold
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  3. Nicolas H Thomä
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Correspondence to Nicolas H Thomä.

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Walczak, M., Petzold, G. & Thomä, N. You can glue it too!. Nat Chem Biol 13, 452–453 (2017). https://doi.org/10.1038/nchembio.2355

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