Cyclin-dependent protein kinases (CDKs) regulate the eukaryotic cell cycle progression. Dysregulated cell cycle leading to unscheduled cell proliferation is a characteristic of many cancer subtypes. Since some tumor cells require… Click to show full abstract
Cyclin-dependent protein kinases (CDKs) regulate the eukaryotic cell cycle progression. Dysregulated cell cycle leading to unscheduled cell proliferation is a characteristic of many cancer subtypes. Since some tumor cells require specific interphase CDKs for proliferation, understanding CDKs activation mechanisms and their differential recognition of cognate cyclins and substrate proteins are essential for developing selective CDK inhibitors for cancer treatments. To date, while the crystal structure of the active CDK2 in complex with cyclin-E is available, no crystal structure for active CDK4 with its cognate cyclin-D is resolved. Here, we model the CDK4/cyclin-D complex as well as CDK2 in complex with cyclin-E to study the conformational dynamics and activation processes of G1 and G1/S phases CDKs, respectively. Extensive molecular dynamics (MD) simulations were performed for both CDK complexes with the kinases in different transition states to resolve the differences in their allosteric regulations at the atomic level. We illustrate that the inactive CDK4 in complex with cyclin-D is in the intermediate state on its pathway to activation in contrast to the fully active CDK2 in complex with cyclin-E, suggesting its activation mechanism is distinct from that of CDK2. This suggests that additional steps such as ATP binding, extension of the activation loop (A-loop), rotation of αC-helix towards “IN” conformation, phosphorylation of A-loop, and substrate binding are required for CDK4. CDK2 interacts with cyclin-E through a large interfacial area (or interface) that stabilizes the protein-protein interaction, while CDK4 has a smaller interfacial area (or interface) in the interaction with cyclin-D. Our simulations affirm experimental data on the current understanding of activation mechanisms of CDK2 and CDK4 and reveal additional atomistical characteristics of their dynamics and activations. Our works report the complete activation mechanisms of CDK2/4, providing insights into the inhibition of these complexes at an atomic level, and are useful for identifying potential targets for drug discovery in oncology. Citation Format: Wengang Zhang, Yonglan Liu, Mingzhen Zhang, Hyunbum Jang, Ruth Nussinov. Deciphering the activation mechanism of CDK4/cyclin-D complex that differs from the CDK2/cyclin-E complex [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 872.
               
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