Structure of a DNA-bound Ultrabithorax-Extradenticle homeodomain complex

Nature. 1999 Feb 25;397(6721):714-9. doi: 10.1038/17833.

Abstract

During the development of multicellular organisms, gene expression must be tightly regulated, both spatially and temporally. One set of transcription factors that are important in animal development is encoded by the homeotic (Hox) genes, which govern the choice between alternative developmental pathways along the anterior-posterior axis. Hox proteins, such as Drosophila Ultrabithorax, have low DNA-binding specificity by themselves but gain affinity and specificity when they bind together with the homeoprotein Extradenticle (or Pbxl in mammals). To understand the structural basis of Hox-Extradenticle pairing, we determine here the crystal structure of an Ultrabithorax-Extradenticle-DNA complex at 2.4 A resolution, using the minimal polypeptides that form a cooperative heterodimer. The Ultrabithorax and Extradenticle homeodomains bind opposite faces of the DNA, with their DNA-recognition helices almost touching each other. However, most of the cooperative interactions arise from the YPWM amino-acid motif of Ultrabithorax-located amino-terminally to its homeodomain-which forms a reverse turn and inserts into a hydrophobic pocket on the Extradenticle homeodomain surface. Together, these protein-DNA and protein-protein interactions define the general principles by which homeotic proteins interact with Extradenticle (or Pbx1) to affect development along the anterior-posterior axis of animals.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Crystallography, X-Ray
  • DNA / chemistry*
  • DNA / metabolism
  • DNA-Binding Proteins / chemistry*
  • DNA-Binding Proteins / metabolism
  • Drosophila
  • Drosophila Proteins*
  • Homeodomain Proteins / chemistry*
  • Homeodomain Proteins / metabolism
  • Insect Proteins / chemistry
  • Insect Proteins / metabolism
  • Macromolecular Substances
  • Models, Molecular
  • Molecular Sequence Data
  • Nucleic Acid Conformation
  • Protein Binding
  • Protein Conformation
  • Transcription Factors / chemistry*
  • Transcription Factors / metabolism

Substances

  • DNA-Binding Proteins
  • Drosophila Proteins
  • Homeodomain Proteins
  • Insect Proteins
  • Macromolecular Substances
  • Transcription Factors
  • Ubx protein, Drosophila
  • exd protein, Drosophila
  • DNA

Associated data

  • PDB/1B81