Discovery and identification of Cdc37-derived peptides targeting the Hsp90-Cdc37 protein-protein interaction
Discovery and identification of Cdc37-derived peptides targeting the Hsp90-Cdc37 protein-protein interaction
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发现和鉴定针对 Hsp90-Cdc37 蛋白-蛋白相互作用的 Cdc37 衍生肽
DOI：
10.1039/c5ra20408a
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发表时间：
2015
期刊：
影响因子：
3.9
通讯作者：
Sun Hao Peng
中科院分区：
文献类型：
--
作者：
Wang Lei;Bao Qi Chao;Xu Xiao Li;Jiang Fen;Gu Kai;Jiang Zheng Yu;Zhang Xiao Jin;Guo Xiao Ke;You Qi Dong;Sun Hao Peng
作为一个有吸引力的抗癌靶点，Hsp90伴侣机器调节着广泛的癌蛋白。大多数临床试验中的Hsp90抑制剂使用相同的ATP阻断机制，而Hsp90-辅酶伴侣复合体的研究进展甚微。Hsp90-CDC37 PPI是一种潜在的癌症治疗靶点，与许多蛋白激酶相关，以实现折叠和成熟。为了探索Hsp90-CDC37结合界面的关键残基，为进一步设计多肽抑制剂提供依据，采用了分子动力学模拟和MM-PBSA分析相结合的策略。随后设计和鉴定了直接来自CDC37结合界面的11个残基的多肽(PEP-1)，其结合容量为6.9μM，ATPase抑制率为3.0μM。这是首次有证据表明，多肽抑制剂不仅可以干扰Hsp90 ATPase的活性，还可以破坏CDC37-Hsp90 PPI。
As an attractive anticancer target, the Hsp90 chaperone machine regulates a wide range of oncoproteins. Most of the Hsp90 inhibitors in clinical trials employ the same ATP blockage mechanism while little progress has been achieved with Hsp90–cochaperone complexes. Numerous protein kinases associate with the Hsp90–Cdc37 PPI, a potential target for the treatment of cancers, to implement folding and maturation. In order to explore the key residues of the Hsp90–Cdc37 binding interface for further design of peptide inhibitors, a combined strategy of molecular dynamics simulation and MM-PBSA analysis was performed. Subsequent design and identification of an eleven-residue peptide (Pep-1) directly derived from the Cdc37 binding interface was achieved to exhibit a 6.9 μM binding capacity and 3.0 μM ATPase inhibitory rate. This is the first evidence that a peptide inhibitor not only interferes with Hsp90 ATPase ability but also disrupts the Cdc37–Hsp90 PPI.