title: Structural basis for an unexpected mode of SERM-mediated ER antagonism.
abstract: Tamoxifen is effective for the prevention and treatment of estrogen-dependent breast cancers, but is associated with an increased incidence of endometrial tumors. We report the crystal structure of the estrogen receptor alpha (ERalpha) ligand binding domain (LBD) bound to the structurally similar compound GW5638, which has therapeutic potential and does not stimulate the uterus. Like tamoxifen, GW5638 relocates the carboxy-terminal helix (H12) to the known coactivator-docking site in the ERalpha LBD. However, GW5638 repositions residues in H12 through specific contacts with the N terminus of this helix. In contrast to tamoxifen, the resulting increase in exposed hydrophobic surface of ERalpha LBD correlates with a significant destabilization of ERalpha in MCF-7 cells. Thus, the GW5638-ERalpha LBD structure reveals an unexpected mode of SERM-mediated ER antagonism, in which the stability of ERalpha is decreased through an altered position of H12. This dual mechanism of antagonism may explain why GW5638 can inhibit tamoxifen-resistant breast tumors.
authors.affiliation: The Ben May Institute for Cancer Research and Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, Illinois 60637, USA.
authors.forename: Ya-Ling
authors.initials: YL
authors.lastname: Wu
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Yang
authors.forename: Zhong
authors.initials: Z
authors.lastname: Ren
authors.forename: Donald P
authors.initials: DP
authors.lastname: McDonnell
authors.forename: John D
authors.initials: JD
authors.lastname: Norris
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Willson
authors.forename: Geoffrey L
authors.initials: GL
authors.lastname: Greene
mesh_terms: D000595:Amino Acid Sequence; D002934:Cinnamates / Q000737:chemistry / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D020845:Selective Estrogen Receptor Modulators / Q000737:chemistry / Q000494:pharmacology*; D013267:Stilbenes / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D002934:Cinnamates; D047628:Estrogen Receptor alpha; D008024:Ligands; D020845:Selective Estrogen Receptor Modulators; D013267:Stilbenes; C087550:3-(4-(1,2-diphenylbut-1-enyl)phenyl)acrylic acid