![]() ![]() Polyubiquitylation is a vital cellular process, which contributes to the regulation of protein homeostasis. Nonetheless, this has not been observed to hamper targeted protein degradation by PROTACs. It is important to note that another class of enzymes called deubiquitinases can counteract this process by removing ubiquitin from target proteins. This complex can enable the E3 ligase to transfer a protein called ubiquitin to the target protein – in fact, multiple molecules of ubiquitin are transferred, both to multiple sites and sequentially to build chains. The consequence of this ternary complex is the induced proximity of the target and E3 ligase, enabling formation of novel protein–protein interactions between target and ligase, which would not otherwise occur in the absence of the PROTAC. Once bound, this binary complex will hunt down the other protein, which binds to the other end of the PROTAC, resulting in formation of a ternary (1:1:1) complex. ![]() The PROTAC can form a binary (i.e., 1:1) interaction (reversible or irreversible) with either of these proteins first. Once inside the cell, the next step is recruitment of the E3 ligase and the protein of interest. Ever since, PROTACs and the wider field of targeted protein degradation have expanded exponentially, with many groups around the world developing degraders as chemical tools to study proteins and as drug candidates for the treatment of diseases. However, interest in PROTACs did not pick up until 2015 when improved molecules were developed by the laboratories of Jay Bradner, Alessio Ciulli and Craig Crews. This concept originated in the late 1990s and the first PROTAC was reported in 2001 by the laboratories of Craig Crews and Raymond Deshaies. The key to PROTACs is their bifunctionality: they simultaneously bind a target protein and an E3 ligase protein, which then ubiquitylates the target, marking it for proteasomal degradation. Proteolysis Targeting Chimeras (or PROTACs) are protein degraders, which utilize the cell’s own waste disposal machinery to eliminate instead of inhibit a target protein. Those with a keen interest in targeting proteins, from chemical biologists to drug hunters alike, cannot help but take notice that a new type of molecule is making waves across this research space. ![]()
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