Introduction to protein degradation

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Scientists have identified numerous proteins that are potential therapeutic targets. However, developing selective and effective therapeutics to target certain proteins has proven difficult due to their uninhabitable nature. Typically, small molecule drugs bind to functional sites on proteins. These sites are often conserved in enzyme families, which puts limits on the selectivity of drugs like kinase inhibitors. Targeted protein degradation has emerged as an advanced approach to reducing protein levels, and it can be selective for even the most difficult targets. The ubiquitin proteasome pathway (UPP) is a normal cellular process responsible for degradation of defective or surplus proteins. The UPP, involves 3 enzymes, E1, E2 and E3 ligase that mark the target protein with a polyubiquitin chain, directing them to the proteasome for degradation. Targeted protein degradation can help us understand the scientific value of targeted proteins. An example targeting the UPP is use of proteolysis targeting chimeras [2]. A proteolysis-targeting chimera can bind to both a protein of interest and a specific ubiquitin ligase, often E3 ligase, and bring them into close proximity. Successful complexation leads to ubiquitination and subsequent degradation of the protein. Proteolysis-targeting chimeras have been developed to study difficult targets, such as BRD4 and CDK9. Modulating the UPP can help reveal the effects of disease-related protein removal for difficult-to-target proteins and protein variants within minutes or hours, and it can be done in a reversible manner. Thermo Fisher Scientific has built the Protein Degradation Resource Center, an educational site that houses information about protein degradation pathways, assays, and assay reagents to support you in discovering your next therapeutic target.

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