help button home button Endocrine Society Molecular Endocrinology ENDO 08 Sessions Library
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH
This version published online on August 28, 2003
Molecular Endocrinology, doi:10.1210/me.2003-0239
Molecular Endocrinology Vol. 0, No. 2003 200302391-
doi:10.1210/me.2003-0239
Copyright © 2003 by the Endocrine Society.
This Article
Right arrow Author Manuscript (PDF)
Right arrow All Versions of this Article:
17/12/2593    most recent
Author Manuscript (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow NURSA Molecule Pages Link
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Tamrazi, A.
Right arrow Articles by Katzenellenbogen, J. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Tamrazi, A.
Right arrow Articles by Katzenellenbogen, J. A.

Submitted on June 19, 2003
Accepted on August 20, 2003

MOLECULAR SENSORS OF ESTROGEN RECEPTOR CONFORMATIONS AND DYNAMICS

Anobel Tamrazi1, Kathryn E. Carlson1, and John A. Katzenellenbogen1*

1 Department of Chemistry, University of Illinois, Urbana, IL 61801

* To whom correspondence should be addressed. E-mail: jkatzene{at}uiuc.edu.

The ligand-induced conformation of a nuclear receptor (NR) ligand-binding domain (LBD) is a principal factor leading to transcriptional activity and determining the pharmacological response. Using the estrogen receptor (ER) LBD labeled site-specifically with a fluorophore, we demonstrate that effects of ligand binding on the conformation and dynamics of this domain can be studied directly, in a quantitative and convenient fashion, by various fluorescence methods. Estrogen ligands of different pharmacological character -agonists, selective estrogen receptor modulators (SERMs), and pure antagonists -each produce distinctive spectroscopic signatures, characteristic of the conformational or dynamic features of their ER-LBD complexes. We can directly follow the equilibrium of helix 12 positions through the degree of local fluorophore rotational freedom and receptor helicity near the C-terminus of helix 11. We observe differences even between ligands within a specific pharmacological class, such as the SERMs raloxifene and trans-4-hydroxytamoxifen, highlighting the ability of these fluorescent receptor sensors to detect unique ER conformations induced even by closely related ligands, yet ones that produce distinctive biological activities in estrogen target cells. Fluorophore-labeled LBDs can serve as versatile molecular sensors predictive of ligand pharmacological character, and should be broadly applicable to other members of the NR superfamily.
Key words: estrogen receptor • fluorescence • conformation • anisotropy • proteolysis • dynamics

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα
Ligands:   17β-Estradiol  |  4-Hydroxytamoxifen  |  Raloxifene



This article has been cited by other articles:


Home page
 EndocrinologyHome page
O. Khalid, S. K. Baniwal, D. J. Purcell, N. Leclerc, Y. Gabet, M. R. Stallcup, G. A. Coetzee, and B. Frenkel
Modulation of Runx2 Activity by Estrogen Receptor-{alpha}: Implications for Osteoporosis and Breast Cancer
Endocrinology, December 1, 2008; 149(12): 5984 - 5995.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Endocrinol.Home page
M. T. Sonoda, L. Martinez, P. Webb, M. S. Skaf, and I. Polikarpov
Ligand Dissociation from Estrogen Receptor Is Mediated by Receptor Dimerization: Evidence from Molecular Dynamics Simulations
Mol. Endocrinol., July 1, 2008; 22(7): 1565 - 1578.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
S. Y. Dai, M. J. Chalmers, J. Bruning, K. S. Bramlett, H. E. Osborne, C. Montrose-Rafizadeh, R. J. Barr, Y. Wang, M. Wang, T. P. Burris, et al.
Prediction of the tissue-specificity of selective estrogen receptor modulators by using a single biochemical method
PNAS, May 20, 2008; 105(20): 7171 - 7176.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Endocrinol.Home page
B. G. Shearer, D. J. Steger, J. M. Way, T. B. Stanley, D. C. Lobe, D. A. Grillot, M. A. Iannone, M. A. Lazar, T. M. Willson, and A. N. Billin
Identification and Characterization of a Selective Peroxisome Proliferator-Activated Receptor {beta}/{delta} (NR1C2) Antagonist
Mol. Endocrinol., February 1, 2008; 22(2): 523 - 529.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Endocrinol.Home page
M. Lupien, M. Jeyakumar, E. Hebert, K. Hilmi, D. Cotnoir-White, C. Loch, A. Auger, G. Dayan, G.-A. Pinard, J.-M. Wurtz, et al.
Raloxifene and ICI182,780 Increase Estrogen Receptor-{alpha} Association with a Nuclear Compartment via Overlapping Sets of Hydrophobic Amino Acids in Activation Function 2 Helix 12
Mol. Endocrinol., April 1, 2007; 21(4): 797 - 816.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Endocrinol.Home page
A. Tamrazi, K. E. Carlson, A. L. Rodriguez, and J. A. Katzenellenbogen
Coactivator Proteins as Determinants of Estrogen Receptor Structure and Function: Spectroscopic Evidence for a Novel Coactivator-Stabilized Receptor Conformation
Mol. Endocrinol., June 1, 2005; 19(6): 1516 - 1528.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
H. Greschik, R. Flaig, J.-P. Renaud, and D. Moras
Structural Basis for the Deactivation of the Estrogen-related Receptor {gamma} by Diethylstilbestrol or 4-Hydroxytamoxifen and Determinants of Selectivity
J. Biol. Chem., August 6, 2004; 279(32): 33639 - 33646.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals
Copyright © 2003 by The Endocrine Society