title: Structural plasticity in the oestrogen receptor ligand-binding domain.
abstract: The steroid hormone receptors are characterized by binding to relatively rigid, inflexible endogenous steroid ligands. Other members of the nuclear receptor superfamily bind to conformationally flexible lipids and show a corresponding degree of elasticity in the ligand-binding pocket. Here, we report the X-ray crystal structure of the oestrogen receptor alpha (ERalpha) bound to an oestradiol derivative with a prosthetic group, ortho- trifluoromethlyphenylvinyl, which binds in a novel extended pocket in the ligand-binding domain. Unlike ER antagonists with bulky side groups, this derivative is enclosed in the ligand-binding pocket, and acts as a potent agonist. This work shows that steroid hormone receptors can interact with a wider array of pharmacophores than previously thought through structural plasticity in the ligand-binding pocket.
authors.affiliation: Department of Cancer Biology, The Scripps Research Institute, 5353 Parkside Drive, Jupiter, Florida 33458, USA. knettles@scripps.edu
authors.forename: Kendall W
authors.initials: KW
authors.lastname: Nettles
authors.forename: John B
authors.initials: JB
authors.lastname: Bruning
authors.forename: German
authors.initials: G
authors.lastname: Gil
authors.forename: Erin E
authors.initials: EE
authors.lastname: O'Neill
authors.forename: Jason
authors.initials: J
authors.lastname: Nowak
authors.forename: Yuee
authors.initials: Y
authors.lastname: Guo
authors.forename: Alun
authors.initials: A
authors.lastname: Hughs
authors.forename: Younchang
authors.initials: Y
authors.lastname: Kim
authors.forename: Eugene R
authors.initials: ER
authors.lastname: DeSombre
authors.forename: Robert
authors.initials: R
authors.lastname: Dilis
authors.forename: Robert N
authors.initials: RN
authors.lastname: Hanson
authors.forename: Andrzej
authors.initials: A
authors.lastname: Joachimiak
authors.forename: Geoffrey L
authors.initials: GL
authors.lastname: Greene
mesh_terms: D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004958:Estradiol / Q000737:chemistry / Q000378:metabolism*; D047628:Estrogen Receptor alpha / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary
chemical_list: D047628:Estrogen Receptor alpha; D008024:Ligands; D004958:Estradiol