2ouz
From Proteopedia
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|ACTIVITY= | |ACTIVITY= | ||
|GENE= ESR1, ESR, NR3A1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | |GENE= ESR1, ESR, NR3A1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | ||
| + | |DOMAIN= | ||
| + | |RELATEDENTRY=[[1err|1ERR]], [[1ere|1ERE]] | ||
| + | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2ouz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ouz OCA], [http://www.ebi.ac.uk/pdbsum/2ouz PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2ouz RCSB]</span> | ||
}} | }} | ||
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==Overview== | ==Overview== | ||
Lasofoxifene is a new and potent selective estrogen receptor modulator (SERM). The structural basis of its interaction with the estrogen receptor has been investigated by crystallographic analysis of its complex with the ligand-binding domain of estrogen receptor alpha at a resolution of 2.0 A. As with other SERMs, lasofoxifene diverts the receptor from its agonist-bound conformation by displacing the C-terminal AF-2 helix into the site at which the LXXLL motif of coactivator proteins would otherwise be able to bind. Lasofoxifene achieves this effect by occupying the space normally filled by residue Leu 540, as well as by modulating the conformation of residues of helix 11 (His 524, Leu 525). A well-defined salt bridge between lasofoxifene and Asp 351 suggests that charge neutralization in this region of the receptor may explain the some of the antiestrogenic effects of lasofoxifene. The results suggest general features of ERalpha/SERM recognition, and add a new dimension to efforts to rationalize differences between the biological activity profiles exhibited by these important pharmacological agents. | Lasofoxifene is a new and potent selective estrogen receptor modulator (SERM). The structural basis of its interaction with the estrogen receptor has been investigated by crystallographic analysis of its complex with the ligand-binding domain of estrogen receptor alpha at a resolution of 2.0 A. As with other SERMs, lasofoxifene diverts the receptor from its agonist-bound conformation by displacing the C-terminal AF-2 helix into the site at which the LXXLL motif of coactivator proteins would otherwise be able to bind. Lasofoxifene achieves this effect by occupying the space normally filled by residue Leu 540, as well as by modulating the conformation of residues of helix 11 (His 524, Leu 525). A well-defined salt bridge between lasofoxifene and Asp 351 suggests that charge neutralization in this region of the receptor may explain the some of the antiestrogenic effects of lasofoxifene. The results suggest general features of ERalpha/SERM recognition, and add a new dimension to efforts to rationalize differences between the biological activity profiles exhibited by these important pharmacological agents. | ||
| - | |||
| - | ==Disease== | ||
| - | Known diseases associated with this structure: Atherosclerosis, susceptibility to OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=133430 133430]], Breast cancer OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=133430 133430]], Estrogen resistance OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=133430 133430]], HDL response to hormone replacement, augmented OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=133430 133430]], Migraine, susceptibility to OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=133430 133430]], Myocardial infarction, susceptibility to OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=133430 133430]] | ||
==About this Structure== | ==About this Structure== | ||
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[[Category: Pandit, J.]] | [[Category: Pandit, J.]] | ||
[[Category: Vajdos, F F.]] | [[Category: Vajdos, F F.]] | ||
| - | [[Category: C3D]] | ||
[[Category: estrogen]] | [[Category: estrogen]] | ||
[[Category: nuclear receptor]] | [[Category: nuclear receptor]] | ||
[[Category: serm]] | [[Category: serm]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 04:23:34 2008'' |
Revision as of 01:23, 31 March 2008
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| , resolution 2.000Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | |||||||
| Gene: | ESR1, ESR, NR3A1 (Homo sapiens) | ||||||
| Related: | 1ERR, 1ERE
| ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
Crystal Structure of Estrogen Receptor alpha-lasofoxifene complex
Overview
Lasofoxifene is a new and potent selective estrogen receptor modulator (SERM). The structural basis of its interaction with the estrogen receptor has been investigated by crystallographic analysis of its complex with the ligand-binding domain of estrogen receptor alpha at a resolution of 2.0 A. As with other SERMs, lasofoxifene diverts the receptor from its agonist-bound conformation by displacing the C-terminal AF-2 helix into the site at which the LXXLL motif of coactivator proteins would otherwise be able to bind. Lasofoxifene achieves this effect by occupying the space normally filled by residue Leu 540, as well as by modulating the conformation of residues of helix 11 (His 524, Leu 525). A well-defined salt bridge between lasofoxifene and Asp 351 suggests that charge neutralization in this region of the receptor may explain the some of the antiestrogenic effects of lasofoxifene. The results suggest general features of ERalpha/SERM recognition, and add a new dimension to efforts to rationalize differences between the biological activity profiles exhibited by these important pharmacological agents.
About this Structure
2OUZ is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
The 2.0 A crystal structure of the ERalpha ligand-binding domain complexed with lasofoxifene., Vajdos FF, Hoth LR, Geoghegan KF, Simons SP, LeMotte PK, Danley DE, Ammirati MJ, Pandit J, Protein Sci. 2007 May;16(5):897-905. PMID:17456742
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