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Explaining the inhibition of cyclin-dependent kinase 5 by peptides derived from p25 with molecular dynamics simulations and MM-PBSA

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Abstract

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.

T-loops and the hydrophobic pockets formed by residues from p25 (blue-gray) and cyclin-dependent kinase (CDK) 5 inhibitory peptide (CIP; red) in CDK5/p25/ATP/HHASPRK (green) and in CDK5/CIP/ATP/HHASPRK (orange). Ile153 interacting with p25 and CIP is colored in blue-gray and red, respectively.

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Authors and Affiliations

  1. Department of Mechanical Engineering, National University of Singapore, 9 Engineering Drive 1, 117576, Singapore, Singapore

    Vincent B. C. Tan, Bing Zhang, Kian Meng Lim & Tong Earn Tay

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  1. Vincent B. C. Tan
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  2. Bing Zhang
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  3. Kian Meng Lim
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  4. Tong Earn Tay
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Correspondence to Vincent B. C. Tan.

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Tan, V.B.C., Zhang, B., Lim, K.M. et al. Explaining the inhibition of cyclin-dependent kinase 5 by peptides derived from p25 with molecular dynamics simulations and MM-PBSA. J Mol Model 16, 1–8 (2010). https://doi.org/10.1007/s00894-009-0514-1

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  • DOI: https://doi.org/10.1007/s00894-009-0514-1

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