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

Massimiliano Maletta, Igor Orlov, Pierre Roblin, Yannick Beck, Dino Moras, Isabelle M. L. Billas and Bruno P. Klaholz ()
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Massimiliano Maletta: Centre for Integrative Biology (CBI), IGBMC (Institute of Genetics and of Molecular and Cellular Biology)
Igor Orlov: Centre for Integrative Biology (CBI), IGBMC (Institute of Genetics and of Molecular and Cellular Biology)
Pierre Roblin: SOLEIL Synchrotron, L’Orme des Merisiers Saint-Aubin
Yannick Beck: Institut de recherche de l’Ecole de biotechnologie de Strasbourg, UMS 3286-Plateforme de Chimie Biologique Intégrative de Strasbourg, Université de Strasbourg
Dino Moras: Centre for Integrative Biology (CBI), IGBMC (Institute of Genetics and of Molecular and Cellular Biology)
Isabelle M. L. Billas: Centre for Integrative Biology (CBI), IGBMC (Institute of Genetics and of Molecular and Cellular Biology)
Bruno P. Klaholz: Centre for Integrative Biology (CBI), IGBMC (Institute of Genetics and of Molecular and Cellular Biology)

Nature Communications, 2014, vol. 5, issue 1, 1-7

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms5139

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