Cryo-EM structure of the complex between DCAF16 (red), DDB1(ΔBPB) (purple), DDA1 (orange), and SMARCA2 BD (green), glued by compound 1 (gray). Credit: Dmitri Segal Most drugs work by inhibition: they block a protein's activity but leave the protein itself intact. Targeted protein degradation takes a fundamentally different approach, harnessing the cell's own quality-control machinery to remove proteins entirely. To do this, degrader molecules bring a target protein into proximity with an E3 ligase—an enzyme complex that labels proteins for destruction by the proteasome. This strategy has transformed drug discovery, particularly because it allows researchers to tackle proteins that are difficult to inhibit directly and to eliminate not only their enzymatic activity but also their structural functions. A new layer of control in protein degradation Until now, however, most degraders have relied on a single ligase.…