The goal of this project is to determine the mechanism of action of hormone-regulatedtranscription factors, called nuclear receptors (NR) at the atomic level. Hormonalmolecules such as glucocorticoids, retinoids, thyroid and vitamin-derived hormones exerttheir effects by regulating the transcription of hormone-responsive target genes withinthe nucleus of cells. These hormones function by directly binding to and modulating theactivity of NRs. These hormone-regulated proteins direct almost every aspect of humanphysiology and improper function can lead to several disease states such as prostateand breast cancer, diabetes, obesity, heart disease, osteoporosis, and processesassociated with aging. NRs often function as heterodimers such as the thyroid receptor:retinoid X receptor (TR:RXR) and the constitutive androstane receptor (CAR:RXR)complexes where TR, CAR and RXR can each recognize specific hormonal signals.Despite the wealth of data on the genetics and cellular localization of NRs, there isrelatively little known of the precise molecular mechanisms of regulation of theseproteins. The ligand binding domain (LBD) of these receptors is central to the allosterythat is essential for NR transactivation. Using a combination of biophysical tools and cell-based transcription assays this project will determine the how hormone-binding andpoint mutations at distant sites can affect the recruitment of co-regulatory proteins andhow the two hormone-binding sites communicate to regulate the transcriptional activityof heterodimeric TR:RXR and CAR:RXR. Structures will be determined by X-raycrystallography to guide biophysical analyses of conformational movements andtranscriptional activity. An important consequence of these studies on the structure anddynamics of NRs is the potential for developing more effective therapies.
This project aims to integrate structural information with biophysical methods, mutagenesis and cell-based assays to explore the basis of allostery within nuclear receptors. Our initial focus will be on the ligand binding domains of the thyroid receptor, (TR), the constitutive androstane receptor (CAR) and the retinoid X receptor (RXR). An important consequence of these studies on the structure and dynamics of these proteins is the potential for developing more effective therapies.
| Clark, Alexander K; Wilder, J Heath; Grayson, Aaron W et al. (2016) The Promiscuity of Allosteric Regulation of Nuclear Receptors by Retinoid X Receptor. J Phys Chem B 120:8338-45 |
| Johnson, Quentin R; Lindsay, Richard J; Nellas, Ricky B et al. (2015) Mapping allostery through computational glycine scanning and correlation analysis of residue-residue contacts. Biochemistry 54:1534-41 |
| Pavlin, Mark Remec; Brunzelle, Joseph S; Fernandez, Elias J (2014) Agonist ligands mediate the transcriptional response of nuclear receptor heterodimers through distinct stoichiometric assemblies with coactivators. J Biol Chem 289:24771-8 |
