Slower CDK4 and faster CDK2 activation in the cell cycle

Wengang Zhang; Yonglan Liu; Hyunbum Jang; Ruth Nussinov

doi:10.1016/j.str.2024.04.012

Slower CDK4 and faster CDK2 activation in the cell cycle

Structure. 2024 Apr 23:S0969-2126(24)00138-2. doi: 10.1016/j.str.2024.04.012. Online ahead of print.

Authors

Wengang Zhang¹, Yonglan Liu¹, Hyunbum Jang², Ruth Nussinov³

Affiliations

¹ Cancer Innovation Laboratory, National Cancer Institute, Frederick, MD 21702, USA.
² Computational Structural Biology Section, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
³ Computational Structural Biology Section, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA; Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. Electronic address: nussinor@mail.nih.gov.

PMID: 38703777
DOI: 10.1016/j.str.2024.04.012

Abstract

Dysregulation of cyclin-dependent kinases (CDKs) impacts cell proliferation, driving cancer. Here, we ask why the cyclin-D/CDK4 complex governs cell cycle progression through the longer G1 phase, whereas cyclin-E/CDK2 regulates the shorter G1/S phase transition. We consider available experimental cellular and structural data including cyclin-E's high-level burst, sustained duration of elevated cyclin-D expression, and explicit solvent molecular dynamics simulations of the inactive monomeric and complexed states, to establish the conformational tendencies along the landscape of the distinct activation scenarios of cyclin-D/CDK4 and cyclin-E/CDK2 in the G1 phase and G1/S transition of the cell cycle, respectively. These lead us to propose slower activation of cyclin-D/CDK4 and rapid activation of cyclin-E/CDK2. We provide the mechanisms through which this occurs, offering innovative CDK4 drug design considerations. Our insightful mechanistic work addresses a compelling cell cycle regulation question and illuminates the distinct activation speeds between the G1 and the G1/S phases, which are crucial for function.

Keywords: CDK inhibitor; CDKs; G1 cell cycle phase; G1/S transition; activation mechanism; allosteric drug discovery; cancer; cyclin-dependent kinases.