Several gamma-herpesviruses encode proteins related to the mammalian cyclin
s, regulatory subunits of cyclin-dependent kinases (cdks) essential for cel
l cycle progression. We report a 2.5 Angstrom crystal structure of a full-l
ength oncogenic viral cyclin from gamma-herpesvirus 68 complexed with cdk2.
The viral cyclin binds cdk2 with an orientation different from cyclin A an
d 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 an
d cellular D-type cyclins, suggesting that this structure has wider implica
tions for other cyclin-cdk complexes. The observed resistance of this viral
cyclin-cdk complex to inhibition by the p27(Kip) cdk inhibitor is explaine
d by sequence and conformational variation in the cyclin rendering the p27(
Kip)-binding site on the cyclin subunit non-functional.