{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Zhang W"],"funding":["Intramural NIH HHS","Frederick National Laboratory for Cancer Research","National Cancer Institute","NCI NIH HHS","National Institutes of Health","Center for Cancer Research"],"pagination":["1269-1280.e2"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC11316634"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["32(8)"],"pubmed_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."],"journal":["Structure (London, England : 1993)"],"pubmed_title":["Slower CDK4 and faster CDK2 activation in the cell cycle."],"pmcid":["PMC11316634"],"funding_grant_id":["HHSN261201500003I","Z01 BC010440","Z01 BC010441","HHSN261201500003C"],"pubmed_authors":["Zhang W","Liu Y","Jang H","Nussinov R"],"additional_accession":[]},"is_claimable":false,"name":"Slower CDK4 and faster CDK2 activation in the cell cycle.","description":"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.","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 Aug","modification":"2026-04-12T19:28:33.534Z","creation":"2026-04-07T13:20:57.925Z"},"accession":"S-EPMC11316634","cross_references":{"pubmed":["38703777"],"doi":["10.1016/j.str.2024.04.012"]}}