Design, synthesis, biological activity and structural analysis of cyclic peptide inhibitors targeting the substrate recruitment site of cyclin-dependent kinase complexes
Design, synthesis, biological activity and structural analysis of cyclic peptide inhibitors targeting the substrate recruitment site of cyclin-dependent kinase complexes
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DOI：
10.1039/b409157d
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发表时间：
2004-01-01
影响因子：
3.2
通讯作者：
Fischer, PM
中科院分区：
文献类型：
--
作者：
Andrews, MJI;McInnes, C;Fischer, PM
抑制细胞周期蛋白A和细胞周期蛋白E相关的细胞周期蛋白依赖性激酶-2（CDK 2）活性是通过肿瘤细胞中的E2 F途径选择性诱导凋亡细胞死亡的有效途径。以天然CDK抑制性（CDKI）肿瘤抑制蛋白p27（KIP 1）中的细胞周期蛋白沟识别基序（CRM）为基础，设计合成了一系列环肽，并报道了其生物活性和结构的NMR和X射线晶体学表征。而线性p27（KIP 1）序列肽是比较无效的，侧链到尾的限制被发现是生产性的。确定了构象约束的最佳大环尺寸，模仿p27的分子内氢键系统。各种大环化合物的分子动力学计算表明，环的灵活性和生物活性之间的密切关系。截短的抑制剂肽类似物也证实了引入环状构象约束在亲和力和效力方面是有利的假设。通过测定和解释CDK 2/细胞周期蛋白A（CDK 2A）和受约束的五肽之间的复合物的X射线晶体结构，证明了环状肽与线性肽的效力增加的结构基础。
Inhibition of cyclin A- and cyclin E-associated cyclin-dependent kinase-2 (CDK2) activities is an effective way of selective induction of apoptotic cell death via the E2F pathway in tumour cells. The cyclin groove recognition motif (CRM) in the natural CDK-inhibitory (CDKI) tumour suppressor protein p27(KIP1) was used as the basis for the design and synthesis of a series of cyclic peptides whose biological activity and structural characterisation by NMR and X-ray crystallography is reported. Whereas linear p27(KIP1) sequence peptides were comparatively ineffective, introduction of side chain-to-tail constraints was found to be productive. An optimal macrocyclic ring size for the conformational constraint was determined, mimicking the intramolecular H-bonding system of p27. Molecular dynamics calculations of various macrocycles suggested a close correlation between ring flexibility and biological activity. Truncated inhibitor peptide analogues also confirmed the hypothesis that introduction of a cyclic conformational constraint is favourable in terms of affinity and potency. The structural basis for the potency increase in cyclic versus linear peptides was demonstrated through the determination and interpretation of X-ray crystal structures of complexes between CDK2/cylin A (CDK2A) and a constrained pentapeptide.