Crystal structure of a vFlip-IKKgamma complex: insights into viral activation of the IKK signalosome

Mol Cell. 2008 Jun 6;30(5):620-31. doi: 10.1016/j.molcel.2008.04.029.


Key to the pathogenicity of several viruses is activation of the canonical nuclear factor-kappaB (NF-kappaB) transcriptional pathway. Subversion of this tightly regulated mechanism is achieved through the production of host mimetic viral proteins that deregulate the transcription process. One such protein is ks-vFLIP (produced by the Kaposi's sarcoma herpes virus [KSHV]), which associates with IKKgamma, an essential component of the IKK complex or signalosome. This interaction renders the canonical NF-kappaB pathway constitutively active and has been linked to Kaposi's sarcoma and other malignancies. In order to elucidate the molecular basis underpinning ks-vFLIP-induced activation of the IKK signalosome, we have determined the crystal structure of a complex involving a fragment of IKKgamma bound to ks-vFLIP at 3.2 A. In addition to identifying and subsequently probing the ks-vFLIP-IKKgamma interface, we have also investigated the effects of a mutation implicated in the genetic disorder anhydrotic ectodermal dysplasia with immunodeficiency (EDA-ID).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Crystallography, X-Ray
  • Ectodermal Dysplasia / genetics
  • Ectodermal Dysplasia / metabolism
  • Herpesvirus 8, Human / genetics
  • Herpesvirus 8, Human / physiology*
  • Humans
  • I-kappa B Kinase / chemistry*
  • I-kappa B Kinase / genetics
  • I-kappa B Kinase / metabolism*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • NF-kappa B / metabolism
  • Protein Binding
  • Protein Conformation
  • Sequence Alignment
  • Signal Transduction*
  • Viral Proteins / chemistry*
  • Viral Proteins / genetics
  • Viral Proteins / metabolism*


  • Intracellular Signaling Peptides and Proteins
  • NF-kappa B
  • Viral Proteins
  • viral FLIP protein, Human herpesvirus 8
  • I-kappa B Kinase

Associated data

  • PDB/3CL3