Photoreactive Stapled BH3 Peptides to Dissect the BCL-2 Family Interactome

SummaryDefining protein interactions forms the basis for discovery of biological pathways, disease mechanisms, and opportunities for therapeutic intervention. To harness the robust binding affinity and selectivity of structured peptides for interactome discovery, we engineered photoreactive stapled BH3 peptide helices that covalently capture their physiologic BCL-2 family targets. The crosslinking α helices covalently trap both static and dynamic protein interactors, and enable rapid identification of interaction sites, providing a critical link between interactome discovery and targeted drug design.

Graphical AbstractFigure optionsDownload high-quality image (215 K)Download as PowerPoint slideHighlights
► pSAHBs are α-helical ligands of the BCL-2 family adapted for protein capture
► pSAHBs selectively and irreversibly trap static and transient protein interactors
► Using MS/MS and docking, pSAHBs can precisely localize and define binding interfaces
► Photoreactive stapled peptides link interactome discovery to targeted drug design