Monomeric complex of human orphan estrogen related receptor-2 with DNA: A pseudo-dimer interface mediates extended half-site recognition

Micah D. Gearhart, Signe M.A. Holmbeck, Ronald M. Evans, H. Jane Dyson, Peter E. Wright

Research output: Contribution to journalArticlepeer-review

84 Scopus citations

Abstract

While most nuclear receptors bind DNA as homo or heterodimers, the human estrogen related receptors (hERRs) are members of a subfamily of orphan receptors that bind DNA as monomers. We have determined the solution structure of the DNA binding domain (DBD) of hERR2 bound to its cognate DNA. The structure and base interactions of the core DBD are similar to those of other nuclear receptors. However, high-affinity, sequence-specific DNA binding as a monomer necessitates formation of additional base contacts outside the core DBD. This is accomplished using a modified guanosine-binding "AT-hook" within the C-terminal extension (CTE) flanking the DBD, which makes base-specific minor groove interactions. The structure of the CTE is stabilized both by interactions with the DNA and by packing against a region of the core DBD normally reserved for dimerization. This pseudo-dimer interface provides a basis for the expansion of DNA recognition and suggests a mechanism through which dimerization may have evolved from an ancestral monomeric receptor.

Original languageEnglish (US)
Pages (from-to)819-832
Number of pages14
JournalJournal of Molecular Biology
Volume327
Issue number4
DOIs
StatePublished - Apr 4 2003

Bibliographical note

Funding Information:
We thank Melissa Allen for cloning and expressing the mutant constructs used in the gel shift experiments and Jennifer Ehley for assistance with the gel shift assays. Preliminary work on the DNA bound chemical shift assignments was done by Drs Danilo Casimiro and Daniel Sem. Additionally, we thank David Case, John Chung, Joel Gottesfeld and Linda Tennant for valuable discussions and technical assistance. This work was supported by grant GM36643 from the National Institutes of Health and by the Skaggs Institute for Chemical Biology.

Keywords

  • ERR
  • NMR
  • Nuclear hormone receptor
  • Solution structure

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