Disruption of R2TP-mediated PIKK maturation with de novo designed binders

Subnanomolar-affinity de novo protein binders that occupy the RPAP3-binding site dismantle R2TP, depleting all PIKKs while sparing other RUVBL1/2-containing complexes.

• Why it matters: RUVBL1/2 inhibitors may lack specificity because RUVBL1/2 functions in multiple complexes, risking off-target effects beyond PIKK maturation.
• What they did: The study targeted the RUVBL1/2-RPAP3 interface with engineered binders, then used CryoEM, proteomic, biochemical, and cellular analyses to test R2TP disruption.
• The result: The binders outcompete RPAP3 and trap RUVBL1/2 in a catalytically inactive conformation, enabling selective control of PIKK abundance.