Crystal structure of IRF-3 reveals mechanism of autoinhibition and virus-induced phosphoactivation

Nat Struct Biol. 2003 Nov;10(11):913-21. doi: 10.1038/nsb1002. Epub 2003 Oct 12.


IRF-3, a member of the interferon regulatory factor (IRF) family of transcription factors, functions as a molecular switch for antiviral activity. IRF-3 uses an autoinhibitory mechanism to suppress its transactivation potential in uninfected cells, and virus infection induces phosphorylation and activation of IRF-3 to initiate the antiviral responses. The crystal structure of the IRF-3 transactivation domain reveals a unique autoinhibitory mechanism, whereby the IRF association domain and the flanking autoinhibitory elements condense to form a hydrophobic core. The structure suggests that phosphorylation reorganizes the autoinhibitory elements, leading to unmasking of a hydrophobic active site and realignment of the DNA binding domain for transcriptional activation. IRF-3 exhibits marked structural and surface electrostatic potential similarity to the MH2 domain of the Smad protein family and the FHA domain, suggesting a common molecular mechanism of action among this superfamily of signaling mediators.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Crystallography, X-Ray
  • DNA-Binding Proteins / chemistry*
  • DNA-Binding Proteins / metabolism
  • Humans
  • Interferon Regulatory Factor-3
  • Molecular Sequence Data
  • Phosphorylation
  • Protein Kinases / metabolism
  • Protein Structure, Tertiary
  • Sequence Alignment
  • Static Electricity
  • Transcription Factors / chemistry*
  • Transcription Factors / metabolism


  • DNA-Binding Proteins
  • IRF3 protein, human
  • Interferon Regulatory Factor-3
  • Transcription Factors
  • Protein Kinases

Associated data

  • PDB/1QWT