Molecular Sensors of Estrogen Receptor Conformations and Dynamics

Anobel Tamrazi, Kathryn E. Carlson, John A. Katzenellenbogen

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2593-2602
Number of pages10
JournalMolecular Endocrinology
Volume17
Issue number12
DOIs
StatePublished - Dec 2003
Externally publishedYes

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Estrogen Receptors
Ligands
Pharmacology
Cytoplasmic and Nuclear Receptors
Estrogens
Selective Estrogen Receptor Modulators
Fluorescence

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology, Diabetes and Metabolism

Cite this

Tamrazi, A., Carlson, K. E., & Katzenellenbogen, J. A. (2003). Molecular Sensors of Estrogen Receptor Conformations and Dynamics. Molecular Endocrinology, 17(12), 2593-2602. https://doi.org/10.1210/me.2003-0239

Molecular Sensors of Estrogen Receptor Conformations and Dynamics. / Tamrazi, Anobel; Carlson, Kathryn E.; Katzenellenbogen, John A.

In: Molecular Endocrinology, Vol. 17, No. 12, 12.2003, p. 2593-2602.

Research output: Contribution to journalArticle

Tamrazi, A, Carlson, KE & Katzenellenbogen, JA 2003, 'Molecular Sensors of Estrogen Receptor Conformations and Dynamics', Molecular Endocrinology, vol. 17, no. 12, pp. 2593-2602. https://doi.org/10.1210/me.2003-0239
Tamrazi, Anobel ; Carlson, Kathryn E. ; Katzenellenbogen, John A. / Molecular Sensors of Estrogen Receptor Conformations and Dynamics. In: Molecular Endocrinology. 2003 ; Vol. 17, No. 12. pp. 2593-2602.
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