Structural basis for high-affinity peptide inhibition of human Pin1
Structural basis for high-affinity peptide inhibition of human Pin1
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DOI：
10.1021/cb7000044
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发表时间：
2007-05-01
影响因子：
4
通讯作者：
Noel, Joseph P.
中科院分区：
文献类型：
--
作者：
Zhang, Yan;Daum, Sebastian;Noel, Joseph P.
人类Pin1是细胞周期进程的关键调节因子，在人类癌症中发挥促生长作用。Pin1的高亲和力抑制剂可能为破坏致癌途径提供独特的机会。在这里，我们报告了两个高分辨率的X射线晶体结构的人Pin1结合到非天然肽抑制剂。结合的高亲和力肽的结构确定了Pin1脯氨酰肽异构酶结构域肽结合的I型转角构象和用于高亲和力识别的广泛的分子界面。此外，这些结构表明化学元素，可以进一步提高未来的肽为基础的Pin抑制剂的亲和力和药理学特性。最后，在两种肽复合物中观察到的分子内氢键模拟FK506和雷帕霉素的环状构象。FK506和雷帕霉素都是其他肽基脯氨酰顺反异构酶的临床重要抑制剂。这一比较发现表明，环肽聚酮桥，如FK506和雷帕霉素或类似的连接中发现的，可以显着提高基于结构的Pin1抑制剂的结合亲和力。
Human Pin1 is a key regulator of cell-cycle progression and plays growth-promoting roles in human cancers. High-affinity inhibitors of Pin1 may provide a unique opportunity for disrupting oncogenic pathways. Here we report two high-resolution X-ray crystal structures of human Pin1 bound to non-natural peptide inhibitors. The structures of the bound high-affinity peptides identify a type-I -turn conformation for Pin1 prolyl peptide isomerase domainpeptide binding and an extensive molecular interface for high-affinity recognition. Moreover, these structures suggest chemical elements that may further improve the affinity and pharmacological properties of future peptide-based Pin inhibitors. Finally, an intramolecular hydrogen bond observed in both peptide complexes mimics the cyclic conformation of FK506 and rapamycin. Both FK506 and rapamycin are clinically important inhibitors of other peptidyl-prolyl cis-trans isomerases. This comparative discovery suggests that a cyclic peptide polyketide bridge, like that found in FK506 and rapamycin or a similar linkage, may significantly improve the binding affinity of structure-based Pin1 inhibitors.