Structural Rearrangements in the Thyroid Hormone Receptor Hinge Domain and Their Putative Role in the Receptor Function

Thyroid hormones such as 3,3′,5 triiodo-L-thyronine (T3) control numerous aspects of mammalian development and metabolism. The actions of such hormones are mediated by specific thyroid hormone receptors (TRs). TR belongs to the nuclear receptor family of modular transcription factors that binds to specific DNA-response elements within target promoters. These receptors can function as homo-or heterodimers such as TR:9-cis retinoic acid receptor (RXR). Here, we present the atomic resolution structure of the TRα•T3:RXRα•9-cis retinoic acid (9c) ligand binding domain heterodimer complex at 2.95 Å along with T3 hormone binding and dissociation and coactivator binding studies. Our data provide a structural basis for allosteric communication between T3 and 9c and negative cooperativity between their binding pockets. In this structure, both TR and RXR are in the active state conformation for optimal binding to coactivator proteins. However, the structure of TR•T3 within TR•T3:RXR•9c is in a relative state of disorder, and the observed kinetics of binding show that T3 dissociates more rapidly from TR•T3:RXR•9c than from TR•T3:RXR. Also, coactivator binding studies with a steroid receptor coactivator-1 (receptor interaction domains 1-3) fragment show lower affinities (K a ) for TR•T3:RXR•9c than TR•T3:RXR. Our study corroborates previously reported observations from cell-based and binding studies and offers a structural mechanism for the repression of TR•T3:RXR transactivation by RXR agonists. Furthermore, the recent discoveries of multiple endogenous RXR agonists that mediate physiological tasks such as lipid biosynthesis underscore the pharmacological importance of negative cooperativity in ligand binding within TR:RXR heterodimers.allostery | thyroid receptor

Section: Steroid Receptor Coactivator-1 Shows Diminished Affinity To supporting

confidence: 68%

Structural basis for negative cooperativity within agonist-bound TR:RXR heterodimers

Putcha

Wright

Brunzelle

et al. 2012

“…hTR␤ LBD (202-461) and hTR␣ LBD (148 -410) were expressed as described previously (34). Ligand was added to 5-fold excess after cell disruption by sonication.…”

Section: Methodsmentioning

confidence: 99%

“…hTR␣1 crystals grew in conditions previously described (34). hTR␤1 crystals grew in conditions established for other hTR␤ complexes (7).…”

Section: Methodsmentioning

confidence: 99%

Gaining ligand selectivity in thyroid hormone receptors via entropy

Martı́nez

Nascimento

Nunes

et al. 2009

Self Cite

Triac ͉ design ͉ mobility N uclear receptors (NRs) are conditional transcription factors with important roles in development and disease (1, 2). Although these proteins are targets for existing drugs and pharmaceutical development, structural relationships between subsets of these proteins mean that ligands that target one NR can cross-react with others. This is commonly observed when NRs exist in multiple subtypes, as for thyroid hormone (TH)

“…As discussed above, the possibility that a large fraction of DNAbound TR-containing complexes are unable to transactivate is consistent with the frequent presence of TRBS next to genes that are not regulated by T3. This situation would be another illustration of the allosteric properties of the DNA/nuclear receptors/ ligand/cofactor complexes, where the interface between DNA and nuclear receptors can influence not only the stability of the interaction with DNA but also the recruitment of coactivators and corepressors (10,(46)(47)(48). A recent analysis of regulation by T3 of the TSHβ gene in a pituitary cell line confirmed this general hypothesis, providing a clear example where both receptors can bind proximal sequences, with only TRβ1 being able to regulate transcription (49).…”

Section: Mechanisms Of Tr-mediated Transcriptional Regulationmentioning

confidence: 99%

“…It might also help to predict the possible detrimental side effects of these synthetic ligands in heart and brain (7) and the toxicity of some environmental contaminants supposed to interfere with TR functions (8). The primary sequence and 3D structure of TRα1 and TRβ1 are very similar, although differences are observed for key amino acids in the DNA-binding domain (9)(10)(11)(12). In most in vitro and cellular assays, they behave equally, even if TRα1 has a slightly higher affinity for T3 and is less prone to form homodimers in the absence of ligand (13).…”

mentioning

confidence: 99%

Genome-wide analysis of thyroid hormone receptors shared and specific functions in neural cells

Chatonnet

Guyot

Galand

et al. 2013

110

100

TRα1 and TRβ1, the two main thyroid hormone receptors in mammals, are transcription factors that share similar properties. However, their respective functions are very different. This functional divergence might be explained in two ways: it can reflect different expression patterns or result from different intrinsic properties of the receptors. We tested this second hypothesis by comparing the repertoires of 3,3′,5-triiodo-L-thyronine (T3)-responsive genes of two neural cell lines, expressing either TRα1 or TRβ1. Using transcriptome analysis, we found that a substantial fraction of the T3 target genes display a marked preference for one of the two receptors. So when placed alone in identical situations, the two receptors have different repertoires of target genes. Chromatin occupancy analysis, performed at a genome-wide scale, revealed that TRα1 and TRβ1 cistromes were also different. However, receptor-selective regulation of T3 target genes did not result from receptor-selective chromatin occupancy of their promoter regions. We conclude that modification of TRα1 and TRβ1 intrinsic properties contributes in a large part to the divergent evolution of the receptors' function, at least during neurodevelopment.