A critical role of helix 3–helix 5 interaction in steroid hormone receptor function
- 14 February 2005
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 102 (8), 2707-2712
- https://doi.org/10.1073/pnas.0409663102
Abstract
The ligand-binding domains of steroid hormone receptors possess a conserved structure with 12 alpha-helices surrounding a central hydrophobic core. On agonist binding, a repositioned helix 12 forms a pocket with helix 3 (H3) and helix 5 (H5), where transcriptional coactivators bind. The precise molecular interactions responsible for activation of these receptors remain to be elucidated. We previously identified a H3-H5 interaction that permits progesterone-mediated activation of a mutant mineralocorticoid receptor. We were intrigued to note that the potential for such interaction is widely conserved in the nuclear receptor family, indicating a possible functional significance. Here, we demonstrate via transcriptional activation studies in cell culture that alteration of residues involved in H3-H5 interaction consistently produces a gain of function in steroid hormone receptors. These data suggest that H3-H5 interaction may function as a molecular switch regulating the activity of nuclear receptors and suggest this site as a general target for pharmacologic intervention. Furthermore, they reveal a general mechanism for the creation of nuclear receptors bearing increased activity, providing a potentially powerful tool for the study of physiologic pathways in vivo.Keywords
This publication has 27 references indexed in Scilit:
- Molecular Basis for the Constitutive Activity of Estrogen-related Receptor α-1Published by Elsevier BV ,2001
- Binding of Ligands and Activation of Transcription by Nuclear ReceptorsAnnual Review of Biophysics and Biophysical Chemistry, 2001
- Specific Recognition of Androgens by Their Nuclear ReceptorPublished by Elsevier BV ,2000
- Functional Probing of the Human Glucocorticoid Receptor Steroid-interacting Surface by Site-directed MutagenesisPublished by Elsevier BV ,2000
- Asymmetry in the PPARγ/RXRα Crystal Structure Reveals the Molecular Basis of Heterodimerization among Nuclear ReceptorsMolecular Cell, 2000
- Constitutively active human estrogen receptors containing amino acid substitutions for tyrosine 537 in the receptor proteinMolecular Endocrinology, 1996
- Cysteines 638 and 665 in the hormone binding domain of human glucocorticoid receptor define the specificity to glucocorticoidsBiochemistry, 1995
- CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choiceNucleic Acids Research, 1994
- Pharmacological and functional characterization of human mineralocorticoid and glucocorticoid receptor ligandsEuropean Journal of Pharmacology: Molecular Pharmacology, 1993
- A Single Amino Acid That Determines the Sensitivity of Progesterone Receptors to RU486Science, 1992