Nuclear hormone receptors (NHRs) represent a large and diverse family of ligand-activated transcription factors involved in regulating development, metabolic homeostasis, salt balance and reproductive health. The ligands for these receptors are typically small hydrophobic molecules such as steroid hormones, thyroid hormone, vitamin D3 and fatty acid derivatives. The first NHR structural information appeared ∼20 years ago with the solution and crystal structures of the DNA binding domains and was followed by the structure of the agonist and antagonist bound ligand binding domains of different NHR members. Interestingly, in addition to these defined structural features, it has become clear that NHRs also possess significant structural plasticity. Thus, the dynamic structure of the NHRs was the topic of a recent stimulating and informative FASEB Summer Research Conference held in Vermont.
References
1.
AutonM., BolenD.W., and RosgenJ. (2008). Structural thermodynamics of protein preferential solvation: osmolyte solvation of proteins, aminoacids, and peptidesProteins73, 802–13.
2.
BrzozowskiA. M., PikeA. C., DauterZ., HubbardR. E., BonnT., EngstromO., OhmanL., GreeneG. L., GustafssonJ. A., and CarlquistM. (1997). Molecular basis of agonism and antagonism in the oestrogen receptorNature389, 753–8.
3.
BurzD. S., and ShekhtmanA. (2009). Structural biology: Inside the living cellNature458, 37–8.
4.
CervantesC. F., MarkwickP. R., SueS. C., McCammonJ. A., DysonH. J., and KomivesE. A. (2009). Functional dynamics of the folded ankyrin repeats of I κ B α revealed by nuclear magnetic resonanceBiochemistry48, 8023–31.
5.
ChandraV., HuangP., HamuroY., RaghuramS., WangY., BurrisT. P., and RastinejadF. (2008). Structure of the intact PPAR-γ-RXR-α nuclear receptor complex on DNANature456, 350–356.
6.
CodinaA., LoveJ. D., LiY., LazarM. A., NeuhausD., and SchwabeJ.W. (2005). Structural insights into the interaction and activation of histone deacetylase 3 by nuclear receptor corepressorsProc Natl Acad Sci U S A102, 6009–14.
7.
GarzaA. M. S., KhanS. H., and KumarR. (2009). Site-specific phosphorylation induces functionally active conformation in the intrinsically disordered N-terminal activation function (AF1) domain of the glucocorticoid receptorMol. Cell. Biol.30, 220–230.
8.
HardT., KellenbachE., BoelensR., MalerB. A., DahlmanK., FreedmanL. P., Carlstedt-DukeJ., YamamotoK. R., GustafssonJ. A., and KapteinR. (1990). Solution structure of the glucocorticoid receptor DNA-binding domainScience249, 157–60.
9.
HilserV. J., and ThompsonE. B. (2007). Intrinsic disorder as a mechanism to optimize allosteric coupling in proteinsProc Natl Acad Sci U S A104, 8311–5.
10.
JeongK. W., LeeY. H., and StallcupM. R. (2009). Recruitment of the SW/SNF chromatin remodeling complex to steroid hormone-regulated promoters by nuclear receptor coactivator flightless-IJ Biol Chem284, 29298–309.
11.
JohnS., SaboP. J., JohnsonT. A., SungM. H., BiddieS. C., LightmanS. L., VossT. C., DavisS. R., MeltzerP. S., StamatoyannopoulosJ. A., and HagerG. L. (2008). Interaction of the glucocorticoid receptor with the chromatin landscapeMol Cell29, 611–24.
12.
KrishnanB., and GieraschL. M. (2008). Cross-strand split tetra-Cys motifs as structure sensors in a β-sheet proteinChem Biol15, 1104–15.
13.
KumarR., and ThompsonE. B. (2003). Transactivation functions of the N-terminal domains of nuclear hormone receptors: protein folding and coactivator interactionsMol Endocrinol17, 1–10.
14.
LaveryD. N., and McEwanI. J. (2008). Structural characterization of the native NH2-terminal transactivation domain of the human androgen receptor: a collapsed disordered conformation underlies structural plasticity and protein-induced foldingBiochemistry47, 3360–9.
15.
LuoM., and SimonsS. S.Jr. (2009). Modulation of glucocorticoid receptor induction properties by cofactors in peripheral blood mononuclear cellsHum Immunol70, 785–9.
16.
McEwanI. J., LaveryD., FischerK., and WattK. (2007). Natural disordered sequences in the amino terminal domain of nuclear receptors: lessons from the androgen and glucocorticoid receptorsNucl Recept Signal5, e001.
17.
MeijsingS. H., PufallM. A., SoA.Y., BatesD. L., ChenL., and YamamotoK. R. (2009). DNA binding site sequence directs glucocorticoid receptor structure and activityScience324, 407–10.
18.
NettlesK. W., BruningJ. B., GilG., NowakJ., SharmaS. K., HahmJ. B., KulpK., HochbergR. B., ZhouH., KatzenellenbogenJ. A., KatzenellenbogenB. S., KimY., JoachmiakA., and GreeneG. L. (2008). NFkappaB selectivity of estrogen receptor ligands revealed by comparative crystallographic analysesNat Chem Biol4, 241–7.
19.
RenaudJ. P., RochelN., RuffM., VivatV., ChambonP., GronemeyerH., and MorasD. (1995). Crystal structure of the RAR-γ ligand-binding domain bound to all-trans retinoic acidNature378, 681–9.
20.
SablinE. P., WoodsA., KrylovaI. N., HwangP., IngrahamH. A., and FletterickR. J. (2008). The structure of corepressor Dax-1 bound to its target nuclear receptor LRH-1Proc Natl Acad Sci U S A105, 18390–5.
21.
Schultz-NortonJ. R., ZieglerY. S., LikhiteV. S., YatesJ. R., and NardulliA. M. (2008). Isolation of novel coregulatory protein networks associated with DNA-bound estrogen receptor αBMC Mol Biol9, 97–108.
22.
SchwabeJ.W., ChapmanL., FinchJ.T., and RhodesD. (1993). The crystal structure of the estrogen receptor DNA-binding domain bound to DNA: how receptors discriminate between their response elementsCell75, 567–78.
23.
WissmannM., YinN., MullerJ. M., GreschikH., FodorB. D., JenuweinT., VoglerC., SchneiderR., GuntherT., BuettnerR., MetzgerE., and SchuleR. (2007). Cooperative demethylation by JMJD2C and LSD1 promotes androgen receptor-dependent gene expressionNat Cell Biol9, 347–53.
