1R5K

Human Estrogen Receptor alpha Ligand-Binding Domain In Complex With GW5638

Summary for 1R5K

• Entry DOI: 10.2210/pdb1r5k/pdb
• Descriptor: Estrogen receptor, (2E)-3-{4-[(1E)-1,2-DIPHENYLBUT-1-ENYL]PHENYL}ACRYLIC ACID (3 entities in total)
• Functional Keywords: alpha helix, helical sandwich, dna binding protein
• Biological source: Homo sapiens (human)
• Cellular location: Isoform 1: Nucleus. Isoform 3: Nucleus: P03372
• Total number of polymer chains: 3
• Total formula weight: 90613.97

Authors

Wu, Y.-L.,Yang, X.,Ren, Z.,McDonnell, D.P.,Norris, J.D.,Willson, T.M.,Greene, G.L. (deposition date: 2003-10-10, release date: 2004-11-23, Last modification date: 2023-08-23)

Primary citation

Wu, Y.L.,Yang, X.,Ren, Z.,McDonnell, D.P.,Norris, J.D.,Willson, T.M.,Greene, G.L.
Structural basis for an unexpected mode of SERM-mediated ER antagonism.
Mol.Cell, 18:413-424, 2005

PubMed 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.

PubMed: 15893725
DOI: 10.1016/j.molcel.2005.04.014

Experimental method

X-RAY DIFFRACTION (2.7 Å)