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This version published online on August 24, 2006
Molecular Endocrinology, doi:10.1210/me.2005-0511
A more recent version of this article appeared on December 1, 2006
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Submitted on December 13, 2005
Accepted on August 16, 2006

STRUCTURE OF THE PROGESTERONE RECEPTOR-DNA COMPLEX: NOVEL INTERACTIONS REQUIRED FOR BINDING TO HALF-SITE RESPONSE ELEMENTS

Sarah C Roemer, Douglas C Donham, Lori Sherman, Vickie H. Pon, Dean P Edwards, and Mair E.A. Churchill*

Program in Molecular Biology, University of Colorado at Denver and Health Sciences Center, Department of Pharmacology, University of Colorado at Denver and Health Sciences Center, Department of Pathology, University of Colorado at Denver and Health Sciences Center, Molecular Biology Program, University of Colorado Health Sciences Center

* To whom correspondence should be addressed. E-mail: Mair.Churchill{at}uchsc.edu.

The DNA binding domain (DBD) of nuclear hormone receptors contains a highly conserved globular domain and a less conserved carboxyl terminal extension (CTE). Despite previous observations that the CTEs of some classes of nuclear receptors are structured and interact with DNA outside of the hexanucleotide hormone response element (HRE), there has been no evidence for such a CTE among the steroid receptors. We have determined the structure of the progesterone receptor (PR)-DBD-CTE DNA complex at a resolution of 2.5 Å, which revealed binding of the CTE to the minor groove flanking the HREs. Alanine substitutions of the interacting CTE residues reduced affinity for inverted repeat HREs separated by 3 nucleotides, and essentially abrogated binding to a single HRE. A highly compressed minor groove of the trinucleotide spacer and a novel dimerization interface were also observed. A PR binding site selection experiment revealed sequence preferences in the trinucleotide spacer and flanking DNA. These results taken together support the notion that sequences outside of the HREs influence the DNA binding affinity and specificity of steroid receptors.
Key words: Protein Structure • Progesterone receptor • DNA-Binding • Transcription factors • Crystallography

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα  |  ERβ  |  ERRβ  |  GR  |  MR  |  PR  |  AR



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