title: DNA binding alters coactivator interaction surfaces of the intact VDR-RXR complex.
abstract: The vitamin D receptor (VDR) functions as an obligate heterodimer in complex with the retinoid X receptor (RXR). These nuclear receptors are multidomain proteins, and it is unclear how various domains interact with one another within the nuclear receptor heterodimer. Here, we show that binding of intact heterodimer to DNA alters the receptor dynamics in regions remote from the DNA-binding domains (DBDs), including the coactivator binding surfaces of both co-receptors, and that the sequence of the DNA response element can determine these dynamics. Furthermore, agonist binding to the heterodimer results in changes in the stability of the VDR DBD, indicating that the ligand itself may play a role in DNA recognition. These data suggest a mechanism by which nuclear receptors show promoter specificity and have differential effects on various target genes, providing insight into the function of selective nuclear receptor modulators.
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter, Florida, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Chalmers
authors.forename: Keith R
authors.initials: KR
authors.lastname: Stayrook
authors.forename: Lorri L
authors.initials: LL
authors.lastname: Burris
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Wang
authors.forename: Scott A
authors.initials: SA
authors.lastname: Busby
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Pascal
authors.forename: Ruben D
authors.initials: RD
authors.lastname: Garcia-Ordonez
authors.forename: John B
authors.initials: JB
authors.lastname: Bruning
authors.forename: Monica A
authors.initials: MA
authors.lastname: Istrate
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Kojetin
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Dodge
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Burris
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Griffin
mesh_terms: D000077556:Alitretinoin; D001665:Binding Sites; D004100:Dihydroxycholecalciferols / Q000737:chemistry; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D056920:Nuclear Receptor Coactivator 1 / Q000737:chemistry; D011401:Promoter Regions, Genetic; D054730:Protein Interaction Domains and Motifs; D025941:Protein Interaction Mapping; D055550:Protein Stability; D017434:Protein Structure, Tertiary; D018167:Receptors, Calcitriol / Q000819:agonists / Q000737:chemistry* / Q000378:metabolism; D047488:Retinoid X Receptors / Q000819:agonists / Q000737:chemistry* / Q000378:metabolism; D014212:Tretinoin / Q000737:chemistry
chemical_list: D004100:Dihydroxycholecalciferols; D008024:Ligands; D018167:Receptors, Calcitriol; D047488:Retinoid X Receptors; D000077556:Alitretinoin; D014212:Tretinoin; C538859:NCOA1 protein, human; D056920:Nuclear Receptor Coactivator 1