This Article Full Text Full Text (PDF) All Versions of this Article: 17/12/2593    most recent Author Manuscript (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager NURSA Molecule Pages Link Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tamrazi, A. Articles by Katzenellenbogen, J. A. Search for Related Content PubMed PubMed Citation Articles by Tamrazi, A. Articles by Katzenellenbogen, J. A.

Molecular Sensors of Estrogen Receptor Conformations and Dynamics

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

Address all correspondence and requests for reprints to: John A. Katzenellenbogen, Department of Chemistry, University of Illinois, 600 South Mathews Avenue, Urbana, Illinois 61801. E-mail: jkatzene{at}uiuc.edu.

The ligand-induced conformation of a nuclear receptor 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 ER 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 nuclear receptor superfamily.

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα

Ligands:   17β-Estradiol  |  4-Hydroxytamoxifen  |  Raloxifene

This article has been cited by other articles:

				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]

				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]

				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]

				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]

				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]

				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]