HSP90 functional site recognition mechanism based on peptide derivatives

Heat shock protein 90 (HSP90) is a crucial molecular chaperone responsible for the activation and maturation of client proteins. Targeting HSP90 can effectively inhibit cancer cell proliferation by either competitively occupying the ATP-binding site or disrupting the protein-protein interaction sites between HSP90 and its co-chaperones. Therefore, studying the recognition and function of HSP90 binding sites is essential for molecular discovery. This study focuses on peptide P1, revealing its dual binding mechanism with HSP90. P1 is capable of simultaneously interacting with both the ATP-binding site of HSP90 and the binding interface with the co-chaperone CDC37 (cell division cycle 37). Through ATPase and Co-IP assays, we found that P1 effectively inhibits both ATP activity and the protein interaction between HSP90 and CDC37, providing a novel approach for developing new inhibitors targeting the HSP90 chaperone system.