Crystal structure of a γ‐herpesvirus cyclin–cdk complex

Several γ‐herpesviruses encode proteins related to the mammalian cyclins, regulatory subunits of cyclin‐dependent kinases (cdks) essential for cell cycle progression. We report a 2.5 Å crystal structure of a full‐length oncogenic viral cyclin from γ‐herpesvirus 68 complexed with cdk2. The viral cyclin binds cdk2 with an orientation different from cyclin A and makes several novel interactions at the interface, yet it activates cdk2 by triggering conformational changes similar to cyclin A. Sequences within the viral cyclin N‐terminus lock part of the cdk2 T‐loop within the core of the complex. These sequences and others are conserved amongst the viral and cellular D‐type cyclins, suggesting that this structure has wider implications for other cyclin–cdk complexes. The observed resistance of this viral cyclin–cdk complex to inhibition by the p27 Kip cdk inhibitor is explained by sequence and conformational variation in the cyclin rendering the p27 Kip ‐binding site on the cyclin subunit non‐functional.