title: Doubling the size of the glucocorticoid receptor ligand binding pocket by deacylcortivazol.
abstract: A common feature of nuclear receptor ligand binding domains (LBD) is a helical sandwich fold that nests a ligand binding pocket within the bottom half of the domain. Here we report that the ligand pocket of glucocorticoid receptor (GR) can be continuously extended into the top half of the LBD by binding to deacylcortivazol (DAC), an extremely potent glucocorticoid. It has been puzzling for decades why DAC, which contains a phenylpyrazole replacement at the conserved 3-ketone of steroid hormones that are normally required for activation of their cognate receptors, is a potent GR activator. The crystal structure of the GR LBD bound to DAC and the fourth LXXLL motif of steroid receptor coactivator 1 reveals that the GR ligand binding pocket is expanded to a size of 1,070 A(3), effectively doubling the size of the GR dexamethasone-binding pocket of 540 A(3) and yet leaving the structure of the coactivator binding site intact. DAC occupies only approximately 50% of the space of the pocket but makes intricate interactions with the receptor around the phenylpyrazole group that accounts for the high-affinity binding of DAC. The dramatic expansion of the DAC-binding pocket thus highlights the conformational adaptability of GR to ligand binding. The new structure also allows docking of various nonsteroidal ligands that cannot be fitted into the previous structures, thus providing a new rational template for drug discovery of steroidal and nonsteroidal glucocorticoids that can be specifically designed to reach the unoccupied space of the expanded pocket.
authors.affiliation: Laboratory of Structural Sciences, Van Andel Research Institute, 333 Bostwick Avenue, Grand Rapids, MI 49503, USA.
authors.forename: Kelly
authors.initials: K
authors.lastname: Suino-Powell
authors.forename: Yong
authors.initials: Y
authors.lastname: Xu
authors.forename: Chenghai
authors.initials: C
authors.lastname: Zhang
authors.forename: Yong-Guang
authors.initials: YG
authors.lastname: Tao
authors.forename: W David
authors.initials: WD
authors.lastname: Tolbert
authors.forename: S Stoney
authors.initials: SS
authors.lastname: Simons
authors.forename: H Eric
authors.initials: HE
authors.lastname: Xu
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D001665:Binding Sites / Q000187:drug effects; D018360:Crystallography, X-Ray; D015195:Drug Design; D017405:Herpes Simplex Virus Protein Vmw65 / Q000235:genetics / Q000502:physiology; D051548:Histone Acetyltransferases / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D056920:Nuclear Receptor Coactivator 1; D051958:Nuclear Receptor Coactivator 2 / Q000737:chemistry / Q000378:metabolism; D056921:Nuclear Receptor Coactivator 3; D056918:Nuclear Receptor Coactivators; D015513:Oncogene Proteins / Q000737:chemistry / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry / Q000187:drug effects; D011281:Pregnatrienes / Q000494:pharmacology*; D011485:Protein Binding; D011487:Protein Conformation / Q000187:drug effects; D011965:Receptors, Glucocorticoid / Q000737:chemistry / Q000187:drug effects*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000187:drug effects / Q000502:physiology; D015534:Trans-Activators / Q000737:chemistry / Q000378:metabolism; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism
chemical_list: D017405:Herpes Simplex Virus Protein Vmw65; D008024:Ligands; C111382:NCOA4 protein, human; D051958:Nuclear Receptor Coactivator 2; D056918:Nuclear Receptor Coactivators; D015513:Oncogene Proteins; D010446:Peptide Fragments; D011281:Pregnatrienes; D011965:Receptors, Glucocorticoid; D011993:Recombinant Fusion Proteins; D015534:Trans-Activators; D014157:Transcription Factors; C029415:deacylcortivazol; D051548:Histone Acetyltransferases; C538859:NCOA1 protein, human; C538866:NCOA3 protein, human; D056920:Nuclear Receptor Coactivator 1; D056921:Nuclear Receptor Coactivator 3