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1r5k

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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'''
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===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.
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{{ABSTRACT_PUBMED_15893725}}
==About this Structure==
==About this Structure==
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[[Category: Alpha helix]]
[[Category: Alpha helix]]
[[Category: Helical sandwich]]
[[Category: Helical sandwich]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 07:06:27 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 29 05:31:24 2008''

Revision as of 02:31, 29 July 2008

Image:1r5k.png

Template:STRUCTURE 1r5k

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

Template:ABSTRACT PUBMED 15893725

About this Structure

1R5K is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

Structural basis for an unexpected mode of SERM-mediated ER antagonism., Wu YL, Yang X, Ren Z, McDonnell DP, Norris JD, Willson TM, Greene GL, Mol Cell. 2005 May 13;18(4):413-24. PMID:15893725

Page seeded by OCA on Tue Jul 29 05:31:24 2008

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