Structural basis of dimerization, coactivator recognition and MODY3 mutations in HNF-1alpha

Nat Struct Biol. 2000 Sep;7(9):744-8. doi: 10.1038/78966.


Maturity-onset diabetes of the young type 3 (MODY3) results from mutations in the transcriptional activator hepatocyte nuclear factor-1alpha (HNF-1alpha). Several MODY3 mutations target the HNF-1alpha dimerization domain (HNF-p1), which binds the coactivator, dimerization cofactor of HNF-1 (DCoH). To define the mechanism of coactivator recognition and the basis for the MODY3 phenotype, we determined the cocrystal structure of the DCoH-HNF-p1 complex and characterized biochemically the effects of MODY3 mutations in HNF-p1. The DCoH-HNF-p1 complex comprises a dimer of dimers in which HNF-p1 forms a unique four-helix bundle. Through rearrangements of interfacial side chains, a single, bifunctional interface in the DCoH dimer mediates both HNF-1alpha binding and formation of a competing, transcriptionally inactive DCoH homotetramer. Consistent with the structure, MODY3 mutations in HNF-p1 reduce activator function by two distinct mechanisms.

Publication types

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

MeSH terms

  • Binding Sites
  • Crystallography, X-Ray
  • DNA-Binding Proteins*
  • Diabetes Mellitus, Type 2 / genetics*
  • Dimerization
  • Hepatocyte Nuclear Factor 1
  • Hepatocyte Nuclear Factor 1-alpha
  • Hepatocyte Nuclear Factor 1-beta
  • Humans
  • Hydro-Lyases / antagonists & inhibitors
  • Hydro-Lyases / chemistry
  • Hydro-Lyases / metabolism*
  • Hydrogen Bonding
  • Models, Biological
  • Models, Molecular
  • Mutation / genetics*
  • Nuclear Proteins*
  • Protein Structure, Secondary
  • Substrate Specificity
  • Transcription Factors / chemistry*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcriptional Activation


  • DNA-Binding Proteins
  • HNF1A protein, human
  • HNF1B protein, human
  • Hepatocyte Nuclear Factor 1-alpha
  • Nuclear Proteins
  • Transcription Factors
  • Hepatocyte Nuclear Factor 1
  • Hepatocyte Nuclear Factor 1-beta
  • Hydro-Lyases
  • pterin-4a-carbinolamine dehydratase

Associated data

  • PDB/1F93