Department of Mechanical Engineering, National University of Singapore, 9 Engineering Drive 1, 117576 Singapore, Singapore.
J Mol Model. 2010 Jan;16(1):1-8. doi: 10.1007/s00894-009-0514-1. Epub 2009 May 23.
A cyclin-dependent kinase (CDK) 5 inhibitory peptide (CIP) from p25 was recently reported to inhibit CDK5/p25 activity in vitro but had no effect on endogenous cdc2 kinase activity. This may lead to a specific CDK5 inhibition strategy in the treatment of neurodegeneration. However, the mechanism of the inhibition remains unclear. In this work, molecular dynamics simulations and energy decomposition calculation models were set up to investigate the deregulation mechanisms of CIP on CDK5 activity. The results show that truncation of the N, and C terminals of p25 introduces important conformational changes into a hydrophobic pocket that is crucial for accommodating Ile153 on the activation loop of CDK5. In addition, such truncations lead to distortion and displacement of the activation loop and consequently affect binding of the substrate peptide. New inhibition sites for selectively inhibiting the activity of CDK5 are also suggested.
最近有报道称，来自 p25 的细胞周期蛋白依赖性激酶 (CDK) 5 抑制肽 (CIP) 可在体外抑制 CDK5/p25 的活性，但对内源性 cdc2 激酶活性没有影响。这可能为神经退行性疾病的治疗提供一种特异性 CDK5 抑制策略。然而，其抑制机制尚不清楚。在这项工作中，建立了分子动力学模拟和能量分解计算模型，以研究 CIP 对 CDK5 活性的调节机制。结果表明，p25 的 N 端和 C 端的截断会导致疏水性口袋发生重要的构象变化，该口袋对于容纳 CDK5 激活环上的 Ile153 至关重要。此外，这种截断会导致激活环的扭曲和位移，从而影响底物肽的结合。还提出了新的抑制位点，以选择性抑制 CDK5 的活性。
