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Crystal structure of a gamma-herpesvirus cyclin-cdk complex

G L Card1, P Knowles, H Laman

  • 1Structural Biology and Gene Expression Laboratories, Imperial Cancer Research Fund, 44 Lincoln's Inn Fields, Holborn, London WC2A 3PX, UK.

The EMBO Journal
|June 17, 2000
PubMed

Insights

Gamma-herpesvirus encodes oncogenic viral cyclins that regulate cyclin-dependent kinases (cdks). This study reveals the crystal structure of a viral cyclin-cdk2 complex, explaining its unique activation and resistance to inhibitors.

Area of Science:

  • Structural biology
  • Virology
  • Molecular and cell biology

Background:

  • Gamma-herpesviruses encode proteins mimicking mammalian cyclins, which are crucial for cell cycle regulation via cyclin-dependent kinases (cdks).
  • Understanding viral cyclin interactions with cdks is key to deciphering viral pathogenesis and cell cycle manipulation.

Purpose of the Study:

  • To determine the crystal structure of an oncogenic viral cyclin from gamma-herpesvirus 68 complexed with cdk2.
  • To elucidate the structural basis for viral cyclin-cdk2 activation and its resistance to cellular inhibitors.

Main Methods:

  • X-ray crystallography at 2.5 Å resolution.
  • Structural analysis of the viral cyclin-cdk2 complex.

Main Results:

  • The viral cyclin binds cdk2 in a novel orientation, inducing conformational changes similar to cyclin A for activation.
  • Specific N-terminal sequences of the viral cyclin interact with the cdk2 T-loop, stabilizing the complex.
  • The viral cyclin-cdk2 complex is resistant to p27(KIP:) inhibition due to variations in the inhibitor-binding site.

Conclusions:

  • The unique structure of the viral cyclin-cdk2 complex provides insights into viral manipulation of the cell cycle.
  • Conserved sequences suggest broader implications for understanding D-type cyclin-cdk interactions.
  • Structural differences explain the viral complex's resistance to p27(KIP:) inhibition, offering potential therapeutic targets.

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