Version 1
: Received: 4 April 2024 / Approved: 5 April 2024 / Online: 5 April 2024 (10:12:16 CEST)
How to cite:
Ziada, S.; Diharce, J.; Serillon, D.; Bonnet, P.; Aci-Sèche, S. Highlighting the Major Role of Cyclin C on Cyclin-Dependent Kinase 8 Activity by Molecular Dynamics Simulations. Preprints2024, 2024040426. https://doi.org/10.20944/preprints202404.0426.v1
Ziada, S.; Diharce, J.; Serillon, D.; Bonnet, P.; Aci-Sèche, S. Highlighting the Major Role of Cyclin C on Cyclin-Dependent Kinase 8 Activity by Molecular Dynamics Simulations. Preprints 2024, 2024040426. https://doi.org/10.20944/preprints202404.0426.v1
Ziada, S.; Diharce, J.; Serillon, D.; Bonnet, P.; Aci-Sèche, S. Highlighting the Major Role of Cyclin C on Cyclin-Dependent Kinase 8 Activity by Molecular Dynamics Simulations. Preprints2024, 2024040426. https://doi.org/10.20944/preprints202404.0426.v1
APA Style
Ziada, S., Diharce, J., Serillon, D., Bonnet, P., & Aci-Sèche, S. (2024). Highlighting the Major Role of Cyclin C on Cyclin-Dependent Kinase 8 Activity by Molecular Dynamics Simulations. Preprints. https://doi.org/10.20944/preprints202404.0426.v1
Chicago/Turabian Style
Ziada, S., Pascal Bonnet and Samia Aci-Sèche. 2024 "Highlighting the Major Role of Cyclin C on Cyclin-Dependent Kinase 8 Activity by Molecular Dynamics Simulations" Preprints. https://doi.org/10.20944/preprints202404.0426.v1
Abstract
Dysregulation of the Cyclin-dependent kinase 8 (CDK8) activity has been associated to many diseases including the colorectal and breast cancer. As usual in the CDK family, the activity of CDK8 is controlled by a regulatory protein called cyclin C (CycC). But while human CDK family members are generally activated in two steps that is, the binding of the cyclin to CDK and the phosphorylation of a residue in the CDK activation loop, CDK8 does not require the phosphorylation step to be active. Another peculiarity of CDK8 is its ability to be associated to CycC while adopted an inactive form. These specificities raise the question of the role of CycC in the complex CDK8-CycC, which appears to be more complex than for the other members of CDK family. Through MD simulations and binding free energy calculations, we investigated the effect of CycC on the structure and dynamics of CDK8 on the one hand, and the structural molecular basis of the protein-protein interaction between the two partners on the other hand. We found that CycC has a stabilizing effect on CDK8 and identified specific interaction hotspots within its interaction surface compared to other human CDK/Cyc pairs. Targeting these specific interaction hotspots could be a promising approach in terms of specificity, to effectively disrupt the interaction between CDK8. The simulation of the conformational transition from the inactive to the active form of CDK8 suggests that the residue Glu99 of the CycC may assume the role of the missing phosphorylation step in the activation mechanism of CDK8. In a more general view, these results point the importance of keeping the CycC in computational studies when studying the human CDK8 protein in both the active and the inactive form.
Keywords
CDK8; Cyclin C; Protein-protein interaction; Molecular dynamic simulation; Free energy calculation; Drug design
Subject
Biology and Life Sciences, Biochemistry and Molecular Biology
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
