Genomes and Genes
Nuclear Receptor Interactions on DNA
Principal Investigator: F Rastinejad
Abstract: The human nuclear receptor family consists of 48 transcription factors that mostly utilize hydrophobic ligands to regulate their activities. These proteins each consist of a series of discrete segments, which include an A/B region, a DNA binding domain (DBD), a hinge segment, a ligand binding domain (LBD) and in some cases additional regions. A series of informative crystallographic studies carried out to date have provided important insights into nuclear receptor DBD and LBD structures and functions, but only as isolated domains. There is no structural understanding of intact nuclear receptors that would show how their different regions are wired together to coordinate their complex functions. Aim 1 of the proposal is directed at providing the detailed structural and dynamic properties of the heterodimeric complex involving full-length RXR-alpha/PPAR-gamma proteins in complex with their ligands and assembled on their DNA target site. The other aims of the proposal are directed at another limitation in the nuclear receptor field related to the "orphan" members - whose ligands remain unknown. Nearly half of all the nuclear receptors in humans have remained orphans, decades after their initial cloning and sequencing. Due to the lack of ligand tools to modulate their activities, the functions of these receptors in regulating genes and biological pathways have remained largely unclear. We propose to study the two orphan nuclear receptors most closely related in sequence to PPARs. We have found that these receptors, rev-erb alpha and rev-erb beta, use heme (iron-porphyrin IX) as their common ligand. We propose to study how heme regulates the activities of these receptors in a series of different contexts, and to visualize crystallographically how heme binds to their internal pockets to reshape their interactions with coregulators. The first objective of the proposal is directed at providing the detailed structural and dynamic properties of the complex of full-length RXR-alpha/PPAR-gamma proteins in complex with their ligands and assembled on their DNA target site. The RXR/PPAR complex is a validated drug target for type II diabetes. The second emphasis area is directed at characterizing the ligands, structures and functions of the orphan nuclear receptors: rev-erb alpha/beta which play important roles in psychiatric and metabolic diseases.
Funding Period: ----------------1997 - ---------------2011-
more information: NIH RePORT
- Identification of heme as the ligand for the orphan nuclear receptors REV-ERBalpha and REV-ERBbetaSrilatha Raghuram
Department of Pharmacology and Center for Molecular Design, University of Virginia Health System, 1300 Jefferson Park Avenue, Charlottesville, Virginia 22908 0733, USA
Nat Struct Mol Biol 14:1207-13. 2007..Our results further indicate that heme regulation of REV-ERBs may link the control of metabolism and the mammalian clock...
- Structure of the intact PPAR-gamma-RXR- nuclear receptor complex on DNAVikas Chandra
Department of Pharmacology, and Center for Molecular Design, University of Virginia Health System, 1300 Jefferson Park Avenue, Charlottesville, Virginia 22908 0735, USA
Nature 456:350-6. 2008..The PPAR-gamma LBD cooperates with both DNA-binding domains (DBDs) to enhance response-element binding. The A/B segments are highly dynamic, lacking folded substructures despite their gene-activation properties...
- Structural overview of the nuclear receptor superfamily: insights into physiology and therapeuticsPengxiang Huang
Department of Pharmacology, and Center for Molecular Design, University of Virginia Health System, Charlottesville, VA 22908, USA
Annu Rev Physiol 72:247-72. 2010....
- Digoxin and its derivatives suppress TH17 cell differentiation by antagonizing RORγt activityJun R Huh
Molecular Pathogenesis Program, The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, New York 10016, USA
Nature 472:486-90. 2011..These data indicate that derivatives of digoxin can be used as chemical templates for the development of RORγt-targeted therapeutic agents that attenuate inflammatory lymphocyte function and autoimmune disease...