CDK2 and CDK4: Cell Cycle Functions Evolve Distinct, Catalysis- Competent Conformations, Offering Drug Targets

Authors

• W Zhang
• Y Liu
• H Jang
• R Nussinov

Abstract

CDK4 and CDK2 are key regulators of cell cycle progression from G1 to S phase. Their aberrant signaling can lead to cancer. This study explores how these kinases achieve different catalytic efficiencies, which may be more importantfor cell cycle progression than cyclin-CDK binding specificity. Using experimental data and molecular dynamics simulations, we found CDK4 is more dynamic than CDK2 in key functional areas, cyclin-D's N-terminus acts as an allosteric regulator for CDK4, and CDK4 complex may have lower catalytic efficiency than CDK2, aligning with their respective cell cycle timescales. We propose two drug design strategies: i) Allosteric inhibition targeting CDK4 regulation by cyclin-D; ii) Dynamic entropy-optimized targeting for CDK4. This mechanistic landscape may apply broadly to kinases and offers new approaches for cancer therapy.

Scientific Focus Area: Structural Biology

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