基于多肽衍生物的HSP90功能位点识别机制研究

HSP90 functional site recognition mechanism based on peptide derivatives

HSP90(heat shock protein 90)是一种重要的分子伴侣蛋白,负责客户蛋白的激活和成熟。靶向HSP90可通过竞争性占据ATP位点或者干扰HSP90与共伴侣蛋白之间的蛋白互作位点,进而有效抑制癌细胞增殖。因此,HSP90的位点识别与功能的研究对于分子发现至关重要。本研究聚焦于多肽P1,揭示了其与HSP90之间的双重结合机制,P1能够同时作用于HSP90的ATP结合位点和共伴侣蛋白CDC37(cell division cycle 37)结合界面。通过ATPase实验和Co-IP实验,发现P1具有同时抑制ATP的活性和HSP90-CDC37之间的蛋白互作的能力,这为靶向HSP90伴侣系统的新型抑制剂提供了新思路。

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 HSP90and 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.