[Folding@home] Catching KRAS in the Act: Simulations Reveal New Paths for Targeted Protein Degradation

[BOINC_News]

Mutations in the KRAS protein are among the most common drivers of human cancers, including lung, pancreatic, and colorectal tumors. Despite decades of effort, KRAS has been considered a particularly difficult therapeutic target. A promising new strategy, known as targeted protein degradation (TPD), is beginning to overcome this challenge.

In TPD, small molecules called PROTACs (Proteolysis Targeting Chimeras) eliminate a disease-associated protein rather than simply inhibiting it. PROTACs are built with two binding components: one attaches to the protein of interest, while the other recruits an E3 ligase — a component of the cell’s protein recycling machinery. By bringing these two proteins into proximity, PROTACs promote ubiquitination and subsequent degradation of the disease-causing protein.

A central difficulty in designing PROTACs lies in identifying the productive protein–protein interactions (PPIs) between the target protein and the E3 ligase. These PPIs...


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