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. 2025 Oct 15;437(20):169121.
doi: 10.1016/j.jmb.2025.169121. Epub 2025 Mar 31.

Distinct Allosteric Networks in CDK4 and CDK6 in the Cell Cycle and in Drug Resistance

Wengang Zhang  1 , Devin Bradburn  2 , Gretchen Heidebrink  2 , Yonglan Liu  1 , Hyunbum Jang  3 , Ruth Nussinov  4 , Mardo Kõivomägi  5
Affiliations

Distinct Allosteric Networks in CDK4 and CDK6 in the Cell Cycle and in Drug Resistance

Wengang Zhang et al. J Mol Biol. .

Abstract

Cyclin-dependent kinases 4 and 6 (CDK4 and CDK6) are key regulators of the G1-S phase transition in the cell cycle. In cancer cells, CDK6 overexpression often outcompetes CDK4 in driving cell cycle progression, contributing to resistance against CDK4/6 inhibitors (CDK4/6i). This suggests distinct functional and conformational differences between these two kinases, despite their striking structural and sequence similarities. Understanding the mechanisms that differentiate CDK4 and CDK6 is crucial, as resistance to CDK4/6i-frequently linked to CDK6 overexpression-remains a significant therapeutic challenge. Notably, CDK6 is often upregulated in CDK4/6i-resistant cancers and rapidly proliferating hematopoietic stem cells, underscoring its unique regulatory roles. We hypothesize that their distinct conformational dynamics explain their differences in phosphorylation of retinoblastoma protein, Rb, inhibitor efficacy, and cell cycle control. This leads us to question how their dissimilar conformational dynamics encode their distinct actions. To elucidate their differential activities, molecular mechanisms, and inhibitor binding, we combine biochemical assays and molecular dynamics (MD) simulations. We discover that CDK4 and CDK6 have distinct allosteric networks connecting the β3-αC loop and the G-loop. CDK6 exhibits stronger coupling and shorter path lengths between these regions, resulting in higher kinase activity upon cyclin binding and impacting inhibitor specificity. We also discover an unrecognized role of the unstructured CDK6 C-terminus, which allosterically connects and stabilizes the R-spine, facilitating slightly higher activity. Our findings bridge the gap between the structural similarity and functional divergence of CDK4 and CDK6, advancing the understanding of kinase regulation in cancer biology.

Keywords: G(1) cell cycle phase; G(1)/S transition; allosteric drug discovery; cancer; cyclin-dependent kinases (CDKs).

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Conflict of interest statement

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Update of

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