The palindromic DNA-bound USP/EcR nuclear receptor adopts an asymmetric organization with allosteric domain positioning

Nat Commun. 2014 Jun 19;5:4139. doi: 10.1038/ncomms5139.

Abstract

Nuclear receptors (NRs) regulate gene expression through DNA- and ligand-binding and thus represent crucial therapeutic targets. The ultraspiracle protein/ecdysone receptor (USP/EcR) complex binds to half-sites with a one base pair spaced inverted repeat (IR1), a palindromic DNA response element (RE) reminiscent of IRs observed for vertebrate steroid hormone receptors. Here we present the cryo electron microscopy structure of the USP/EcR complex bound to an IR1 RE which provides the first description of a full IR-bound NR complex. The structure reveals that even though the DNA is almost symmetric, the complex adopts a highly asymmetric architecture in which the ligand-binding domains (LBDs) are positioned 5' off-centred. Additional interactions of the USP LBD with the 5'-flanking sequence trigger transcription activity as monitored by transfection assays. The comparison with DR-bound NR complexes suggests that DNA is the major allosteric driver in inversely positioning the LBDs, which serve as the main binding-site for transcriptional regulators.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Crystallography, X-Ray
  • DNA / genetics*
  • DNA / metabolism
  • DNA-Binding Proteins / chemistry*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Gene Expression Regulation
  • Insect Proteins / chemistry*
  • Insect Proteins / genetics
  • Insect Proteins / metabolism*
  • Inverted Repeat Sequences
  • Moths / chemistry
  • Moths / genetics
  • Moths / metabolism*
  • Protein Binding
  • Protein Structure, Tertiary
  • Receptors, Steroid / chemistry*
  • Receptors, Steroid / genetics
  • Receptors, Steroid / metabolism*
  • Response Elements

Substances

  • DNA-Binding Proteins
  • Insect Proteins
  • Receptors, Steroid
  • ecdysone receptor
  • DNA

Associated data

  • PDB/4UMM