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

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

Author information

1
1] Centre for Integrative Biology (CBI), Department of Integrated Structural Biology, IGBMC (Institute of Genetics and of Molecular and Cellular Biology), 1 rue Laurent Fries, 67404 Illkirch, France [2] Centre National de la Recherche Scientifique (CNRS) UMR 7104, 67404 Illkirch, France [3] Institut National de la Santé et de la Recherche Médicale (INSERM) U964, 67404 Illkirch, France [4] Université de Strasbourg, 67404 Strasbourg, France.
2
1] SOLEIL Synchrotron, L'Orme des Merisiers Saint-Aubin, 91192 Gif-sur-Yvette, France [2] INRA-URBIA, Rue de la Geraudière, 44316 Nantes, France.
3
1] Institut de recherche de l'Ecole de biotechnologie de Strasbourg, UMS 3286-Plateforme de Chimie Biologique Intégrative de Strasbourg, Université de Strasbourg, 67412 Illkirch, France [2] Laboratoire de Biochimie, Ecole Supérieure de Physique et de Chimie Industrielles de la Ville de Paris, 75231 Paris Cedex 05, France.

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.

PMID:
24942373
DOI:
10.1038/ncomms5139
[Indexed for MEDLINE]

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