title: Structure of the full human RXR/VDR nuclear receptor heterodimer complex with its DR3 target DNA.
abstract: Transcription regulation by steroid hormones and other metabolites is mediated by nuclear receptors (NRs) such as the vitamin D and retinoid X receptors (VDR and RXR). Here, we present the cryo electron microscopy (cryo-EM) structure of the heterodimeric complex of the liganded human RXR and VDR bound to a consensus DNA response element forming a direct repeat (DR3). The cryo-EM map of the 100-kDa complex allows positioning the individual crystal structures of ligand- and DNA-binding domains (LBDs and DBDs). The LBDs are arranged perpendicular to the DNA and are located asymmetrically at the DNA 5'-end of the response element. The structure reveals that the VDR N-terminal A/B domain is located close to the DNA. The hinges of both VDR and RXR are fully visible and hold the complex in an open conformation in which co-regulators can bind. The asymmetric topology of the complex provides the structural basis for RXR being an adaptive partner within NR heterodimers, while the specific helical structure of VDR's hinge connects the 3'-bound DBD with the 5'-bound LBD and thereby serves as a conserved linker of defined length sensitive to mutational deletion.
authors.affiliation: Department of Integrated Structural Biology, IGBMC (Institute of Genetics and of Molecular and Cellular Biology), 1 rue Laurent Fries, Illkirch, France.
authors.forename: Igor
authors.initials: I
authors.lastname: Orlov
authors.forename: Natacha
authors.initials: N
authors.lastname: Rochel
authors.forename: Dino
authors.initials: D
authors.lastname: Moras
authors.forename: Bruno P
authors.initials: BP
authors.lastname: Klaholz
mesh_terms: D000077556:Alitretinoin; D000595:Amino Acid Sequence; D002117:Calcitriol / Q000737:chemistry / Q000378:metabolism; D020285:Cryoelectron Microscopy; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D019281:Dimerization; D006801:Humans; D008024:Ligands; D046911:Macromolecular Substances; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D011487:Protein Conformation; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary; D018167:Receptors, Calcitriol / Q000737:chemistry* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry; D047490:Retinoid X Receptor alpha / Q000737:chemistry* / Q000378:metabolism; D014212:Tretinoin / Q000737:chemistry / Q000378:metabolism; D030181:Vitamin D Response Element
chemical_list: D008024:Ligands; D046911:Macromolecular Substances; D018167:Receptors, Calcitriol; D011993:Recombinant Fusion Proteins; D047490:Retinoid X Receptor alpha; D000077556:Alitretinoin; D014212:Tretinoin; D004247:DNA; D002117:Calcitriol