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The orphan nuclear receptor TR4 is a vitamin A-activated nuclear receptor.

Zhou XE, Suino-Powell KM, Xu Y, Chan CW, Tanabe O, Kruse SW, Reynolds R, Engel JD, Xu HE
J Biol Chem 286 2877-85 (2011)
Cited: 52 times
EuropePMC logo PMID: 21068381

Abstract

Testicular receptors 2 and 4 (TR2/4) constitute a subgroup of orphan nuclear receptors that play important roles in spermatogenesis, lipid and lipoprotein regulation, and the development of the central nervous system. Currently, little is known about the structural features and the ligand regulation of these receptors. Here we report the crystal structure of the ligand-free TR4 ligand binding domain, which reveals an autorepressed conformation. The ligand binding pocket of TR4 is filled by the C-terminal half of helix 10, and the cofactor binding site is occupied by the AF-2 helix, thus preventing ligand-independent activation of the receptor. However, TR4 exhibits constitutive transcriptional activity on multiple promoters, which can be further potentiated by nuclear receptor coactivators. Mutations designed to disrupt cofactor binding, dimerization, or ligand binding substantially reduce the transcriptional activity of this receptor. Importantly, both retinol and retinoic acid are able to promote TR4 to recruit coactivators and to activate a TR4-regulated reporter. These findings demonstrate that TR4 is a ligand-regulated nuclear receptor and suggest that retinoids might have a much wider regulatory role via activation of orphan receptors such as TR4.

Reviews - 3p0u mentioned but not cited (2)

  1. Strategies for developing pregnane X receptor antagonists: Implications from metabolism to cancer. Chai SC, Wright WC, Chen T. Med Res Rev 40 1061-1083 (2020)
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Articles - 3p0u mentioned but not cited (6)

  1. The orphan nuclear receptor TR4 is a vitamin A-activated nuclear receptor. Zhou XE, Suino-Powell KM, Xu Y, Chan CW, Tanabe O, Kruse SW, Reynolds R, Engel JD, Xu HE. J. Biol. Chem. 286 2877-2885 (2011)
  2. The crystal structure of the orphan nuclear receptor NR2E3/PNR ligand binding domain reveals a dimeric auto-repressed conformation. Tan MH, Zhou XE, Soon FF, Li X, Li J, Yong EL, Melcher K, Xu HE. PLoS ONE 8 e74359 (2013)
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  5. Structures of human TR4LBD-JAZF1 and TR4DBD-DNA complexes reveal the molecular basis of transcriptional regulation. Liu Y, Ma L, Li M, Tian Z, Yang M, Wu X, Wang X, Shang G, Xie M, Chen Y, Liu X, Jiang L, Wu W, Xu C, Xia L, Li G, Dai S, Chen Z. Nucleic Acids Res 51 1443-1457 (2023)
  6. TAK1 Activation by NLRP3 Deficiency Confers Cardioprotection Against Pressure Overload-Induced Cardiomyocyte Pyroptosis and Hypertrophy. Li X, You J, Dai F, Wang S, Yang FH, Wang X, Ding Z, Huang J, Chen L, Abudureyimu M, Tang H, Yang X, Xiang Y, Backx PH, Ren J, Ge J, Zou Y, Wu J. JACC Basic Transl Sci 8 1555-1573 (2023)


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  4. Retinoic acid has different effects on UCP1 expression in mouse and human adipocytes. Murholm M, Isidor MS, Basse AL, Winther S, Sørensen C, Skovgaard-Petersen J, Nielsen MM, Hansen AS, Quistorff B, Hansen JB. BMC Cell Biol. 14 41 (2013)
  5. Structural insights into gene repression by the orphan nuclear receptor SHP. Zhi X, Zhou XE, He Y, Zechner C, Suino-Powell KM, Kliewer SA, Melcher K, Mangelsdorf DJ, Xu HE. Proc. Natl. Acad. Sci. U.S.A. 111 839-844 (2014)
  6. Discovery of 2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide derivatives as new RORγ inhibitors using virtual screening, synthesis and biological evaluation. Zhang Y, Xue X, Jin X, Song Y, Li J, Luo X, Song M, Yan W, Song H, Xu Y. Eur J Med Chem 78 431-441 (2014)
  7. Discovery of a protein-metabolite interaction between unsaturated fatty acids and the nuclear receptor Nur77 using a metabolomics approach. Vinayavekhin N, Saghatelian A. J. Am. Chem. Soc. 133 17168-17171 (2011)
  8. PGC-1 coactivator activity is required for murine erythropoiesis. Cui S, Tanabe O, Lim KC, Xu HE, Zhou XE, Lin JD, Shi L, Schmidt L, Campbell A, Shimizu R, Yamamoto M, Engel JD. Mol. Cell. Biol. 34 1956-1965 (2014)
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  13. Recent advances in the study of testicular nuclear receptor 4. Ding XF, Yu SC, Chen BD, Lin SJ, Chang C, Li GH. J Zhejiang Univ Sci B 14 171-177 (2013)
  14. Biased, non-equivalent gene-proximal and -distal binding motifs of orphan nuclear receptor TR4 in primary human erythroid cells. Shi L, Sierant MC, Gurdziel K, Zhu F, Cui S, Kolodziej KE, Strouboulis J, Guan Y, Tanabe O, Lim KC, Engel JD. PLoS Genet. 10 e1004339 (2014)
  15. Design, Synthesis, and Actions of an Innovative Bispecific Designer Peptide. Meems LMG, Andersen IA, Pan S, Harty G, Chen Y, Zheng Y, Harders GE, Ichiki T, Heublein DM, Iyer SR, Sangaralingham SJ, McCormick DJ, Burnett JC. Hypertension 73 900-909 (2019)
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  17. Identification of N-phenyl-2-(N-phenylphenylsulfonamido)acetamides as new RORγ inverse agonists: Virtual screening, structure-based optimization, and biological evaluation. Song Y, Xue X, Wu X, Wang R, Xing Y, Yan W, Zhou Y, Qian CN, Zhang Y, Xu Y. Eur J Med Chem 116 13-26 (2016)
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  19. Targeting the TR4 nuclear receptor with antagonist bexarotene can suppress the proopiomelanocortin signalling in AtT-20 cells. Xia L, Shen D, Zhang Y, Lu J, Wang M, Wang H, Chen Y, Xue D, Xie D, Li G. J Cell Mol Med 25 2404-2417 (2021)
  20. Identification of Small-Molecule Regulators of Testicular Receptor 4 via a Drug Repurposing Screening. Xia L, Shen D, Wang H, Ren L, Chen Y, Li G. ACS Omega 5 30625-30632 (2020)
  21. Structural overview and perspectives of the nuclear receptors, a major family as the direct targets for small-molecule drugs. Li F, Song C, Zhang Y, Wu D. Acta Biochim Biophys Sin (Shanghai) 54 12-24 (2022)
  22. BAP1 regulation of the key adaptor protein NCoR1 is critical for γ-globin gene repression. Yu L, Jearawiriyapaisarn N, Lee MP, Hosoya T, Wu Q, Myers G, Lim KC, Kurita R, Nakamura Y, Vojtek AB, Rual JF, Engel JD. Genes Dev. 32 1537-1549 (2018)
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  24. Targeting TR4 nuclear receptor with antagonist bexarotene increases docetaxel sensitivity to better suppress the metastatic castration-resistant prostate cancer progression. Hu L, Sun Y, Luo J, He X, Ye M, Li G, Zhang Y, Bai J, Zhang D, Chang C. Oncogene 39 1891-1903 (2020)
  25. Targeting the TR4 nuclear receptor-mediated lncTASR/AXL signaling with tretinoin increases the sunitinib sensitivity to better suppress the RCC progression. Shi H, Sun Y, He M, Yang X, Hamada M, Fukunaga T, Zhang X, Chang C. Oncogene 39 530-545 (2020)


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