Structures of heterotrimeric cyclin-dependent kinase 4 complexes reveal the mechanism of drug inhibition The activities of cyclin-dependent kinases (CDKs), regulated primarily by the periodic expression of their cyclin binding partners, temporally order sequential cell cycle transitions through G 1 , S phase, G 2 , and mitosis. In mammalian cells, regulators of G 1 transit include three D-type cyclins, as well as CDK4 and CDK6, and the CDK inhibitory proteins, p21 and p27 ( 1 ). In response to mitogens, individual D-type cyclins assemble with CDK4 or CDK6 and, paradoxically, with the p21 or p27 “inhibitors” to yield active higher-order holoenzymes that drive G 1 progression and prime cells to enter S phase and begin DNA replication ( 2 ). On page 1330 of this issue, Guiley et al. ( 3 ) report the crystal structures of trimeric complexes containing cyclin D1, CDK4, and either p27 or p21 and reveal that active trimers containing tyrosine-phosphorylated p27 are surprisingly refractory to the U. S. Food and Drug Administration (FDA)–approved CDK4/6 inhibitors that are used to treat hormone-dependent breast cancer.