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| {{STRUCTURE_1r5k| PDB=1r5k | SCENE= }} | | {{STRUCTURE_1r5k| PDB=1r5k | SCENE= }} |
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| '''Human Estrogen Receptor alpha Ligand-Binding Domain In Complex With GW5638'''
| | ===Human Estrogen Receptor alpha Ligand-Binding Domain In Complex With GW5638=== |
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| ==Overview==
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| 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.
| | The line below this paragraph, {{ABSTRACT_PUBMED_15893725}}, adds the Publication Abstract to the page |
| | (as it appears on PubMed at http://www.pubmed.gov), where 15893725 is the PubMed ID number. |
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| | {{ABSTRACT_PUBMED_15893725}} |
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| ==About this Structure== | | ==About this Structure== |
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| [[Category: Alpha helix]] | | [[Category: Alpha helix]] |
| [[Category: Helical sandwich]] | | [[Category: Helical sandwich]] |
| ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 07:06:27 2008'' | | |
| | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 29 05:31:24 2008'' |