Crystal structure of a gamma-herpesvirus cyclin-cdk complex.
Several gamma-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 A crystal structure of a full-length oncogenic viral cyclin from gamma-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.
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Structural Biology and Gene Expression Laboratories, Imperial Cancer Research Fund, 44 Lincoln's Inn Fields, Holborn, London WC2A 3PX, UK.
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Laman
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McDonald
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D000595:Amino Acid Sequence; D042846:CDC2-CDC28 Kinases; D018797:Cell Cycle Proteins; D018360:Crystallography, X-Ray; D019925:Cyclin A / Q000737:chemistry*; D051357:Cyclin-Dependent Kinase 2; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry*; D016213:Cyclins / Q000737:chemistry*; D004351:Drug Resistance; D018142:Gammaherpesvirinae / Q000737:chemistry*; D008869:Microtubule-Associated Proteins / Q000494:pharmacology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry*; D025521:Tumor Suppressor Proteins; D014764:Viral Proteins / Q000737:chemistry*
D018797:Cell Cycle Proteins; D019925:Cyclin A; D016213:Cyclins; C411568:M cyclin, gamma-herpesvirus 68; D008869:Microtubule-Associated Proteins; D025521:Tumor Suppressor Proteins; D014764:Viral Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases