In the proposed studies, the investigators plan to utilized the structural information to prepare a library of specific mutations designed to systematically alter the TR LBD surface such that interactions with other proteins involved in various TR functions might be disrupted. It is also planned to prepare mutations that should influence the function of two regions termed tau-3 and tau-4 thought to be involved in TR LBD transcriptional activation functions and of a Helix region (Helix-1) that maybe involved in various TR functions. Activities of mutated molecules will be examined through assays of T3 binding (TR + T3) binding to DNA and other proteins and by transfecting genes that express the mutated TRs along with reporter genes and genes that express other proteins that interact with TRs in mammalian cells.
| Yuan, Chaoshen; Nguyen, Phuong; Baxter, John D et al. (2013) Distinct ligand-dependent and independent modes of thyroid hormone receptor (TR)/PGC-1? interaction. J Steroid Biochem Mol Biol 133:58-65 |
| Yumoto, Fumiaki; Nguyen, Phuong; Sablin, Elena P et al. (2012) Structural basis of coactivation of liver receptor homolog-1 by ?-catenin. Proc Natl Acad Sci U S A 109:143-8 |
| Cunha Lima, Suzana T; Rodrigues, Edson D (2011) The oligomeric state of thyroid receptor regulates hormone binding kinetics. J Endocrinol 210:125-34 |
| Figueira, A C M; Saidemberg, D M; Souza, P C T et al. (2011) Analysis of agonist and antagonist effects on thyroid hormone receptor conformation by hydrogen/deuterium exchange. Mol Endocrinol 25:15-31 |
| Martinez, Leandro; Nascimento, Alessandro S; Nunes, Fabio M et al. (2009) Gaining ligand selectivity in thyroid hormone receptors via entropy. Proc Natl Acad Sci U S A 106:20717-22 |
| Cunha Lima, Suzana T; Nguyen, Ngoc-Ha; Togashi, Marie et al. (2009) Differential effects of TR ligands on hormone dissociation rates: evidence for multiple ligand entry/exit pathways. J Steroid Biochem Mol Biol 117:125-31 |
| Jouravel, Natalia; Sablin, Elena; Togashi, Marie et al. (2009) Molecular basis for dimer formation of TRbeta variant D355R. Proteins 75:111-7 |
| Govindan, Manjapra; Meng, Xianwang; Denis, Clyde L et al. (2009) Identification of CCR4 and other essential thyroid hormone receptor co-activators by modified yeast synthetic genetic array analysis. Proc Natl Acad Sci U S A 106:19854-9 |
| Shah, Vanya; Nguyen, Phuong; Nguyen, Ngoc-Ha et al. (2008) Complex actions of thyroid hormone receptor antagonist NH-3 on gene promoters in different cell lines. Mol Cell Endocrinol 296:69-77 |
| Estebanez-Perpina, Eva; Arnold, Leggy A; Arnold, Alexander A et al. (2007) A surface on the androgen receptor that allosterically regulates coactivator binding. Proc Natl Acad Sci U S A 104:16074-9 |
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