Structural basis for the modulation of CDK-dependent/independent activity of cyclin D1.
D-type cyclins are key regulators of the cell division cycle. In association with Cyclin Dependent Kinases (CDK) 2/4/6, they control the G1/S-phase transition in part by phosphorylation and inactivation of tumor suppressor of retinoblastoma family. Defective regulation of the G1/S transition is a well-known cause of cancer, making the cyclin D1-CDK4/6 complex a promising therapeutic target. Our objective is to develop inhibitors that would block the formation or the activation of the cyclin D1-CDK4/6 complex, using in silico docking experiments on a structural homology model of the cyclin D1-CDK4/6 complex. To this end we focused on the cyclin subunit in three different ways: (1) targeting the part of the cyclin D1 facing the N-terminal domain of CDK4/6, in order to prevent the dimer formation; (2) targeting the part of the cyclin D1 facing the C-terminal domain of CDK4/6, in order to prevent the activation of CDK4/6 by blocking the T-loop in an inactive conformation, and also to destabilize the dimer; (3) targeting the groove of cyclin D1 where p21 binds, in order to mimic its inhibition mode by preventing binding of cyclin D1-CDK4/6 complex to its targets. Our strategy, and the tools we developed, will provide a computational basis to design lead compounds for novel cancer therapeutics, targeting a broad range of proteins involved in the regulation of the cell cycle.
Ferrer
Jean-Luc
JL
Laboratoire de Cristallogenèse et Cristallographie des Protéines, Institut de Biologie Structural J.-P Ebel, Grenoble, France. jean-luc.ferrer@ibs.fr
Dupuy
Jérôme
J
Borel
Franck
F
Jacquamet
Lilian
L
Noel
Joseph P
JP
Dulic
Vjekoslav
V
D000595:Amino Acid Sequence; D019938:Cyclin D1 / Q000737:chemistry* / Q000378:metabolism*; D018844:Cyclin-Dependent Kinases / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010802:Phylogeny; D017433:Protein Structure, Secondary; D016415:Sequence Alignment; D055672:Static Electricity; D040681:Structural Homology, Protein; D013329:Structure-Activity Relationship
D019938:Cyclin D1; D018844:Cyclin-Dependent Kinases