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Two resistance to thyroid hormone mutants with impaired hormone binding.

Huber BR, Sandler B, West BL, Cunha Lima ST, Nguyen HT, Apriletti JW, Baxter JD, Fletterick RJ
Mol Endocrinol 17 643-52 (2003)
Cited: 13 times
EuropePMC logo PMID: 12554782

Abstract

Resistance to hormones is commonly due to mutations in genes encoding receptors. Resistance to thyroid hormone is due mostly to mutations of the beta-form of the human (h) thyroid hormone receptor (hTRbeta). We determined x-ray crystal structures of two hTRbeta ligand-binding domains (LBDs), Ala 317 Thr and Arg 316 His. Amino acids 316 and 317 form part of the hormone-binding pocket. The methyl of Ala 317, contacting iodine, sculpts the T3 hormone-binding pocket. Arg 316 is not in direct contact with T3 and has an unknown role in function. Remarkably, the Arg forms part of an unusual buried polar cluster in hTRbeta. Although the identity of the amino acids changes, the polar cluster appears in all nuclear receptors. In spite of the differing roles of 316 and 317, both resistance to thyroid hormone mutants display decreased T3 affinity and weakened transcriptional activation. The two mutants differ in that the Arg 316 His receptor does not form TR-TR homodimers on DNA. 3,5,3'-Triiodothyroacetic acid is bound to both receptors. Thr 317 repositions 3,5,3'-triiodothyroacetic acid distending the face of the receptor that binds coregulators. Arg 316 forms two hydrogen bonds with helix 1. Both are lost with mutation to His displacing helix 1 of the LBD and disordering the loop after helix 1. The stability of the helix 1, deriving in part from the buried polar cluster, is important for hormone binding and formation of TR dimers. The observation that the Arg 316 His mutation affects these functions implies a role for helix 1 in linking hormone binding to the DNA-binding domain-LBD configuration.

Articles - 1nq2 mentioned but not cited (3)

  1. Halogen bonds in biological molecules. Auffinger P, Hays FA, Westhof E, Ho PS. Proc Natl Acad Sci U S A 101 16789-16794 (2004)
  2. Spectrum of disease-causing mutations in protein secondary structures. Khan S, Vihinen M. BMC Struct Biol 7 56 (2007)
  3. Molecular dynamics simulations reveal multiple pathways of ligand dissociation from thyroid hormone receptors. Martínez L, Sonoda MT, Webb P, Baxter JD, Skaf MS, Polikarpov I. Biophys J 89 2011-2023 (2005)


Reviews citing this publication (1)

  1. Conformational adaptation of nuclear receptor ligand binding domains to agonists: potential for novel approaches to ligand design. Togashi M, Borngraeber S, Sandler B, Fletterick RJ, Webb P, Baxter JD. J Steroid Biochem Mol Biol 93 127-137 (2005)

Articles citing this publication (9)

  1. Ligand selectivity by seeking hydrophobicity in thyroid hormone receptor. Borngraeber S, Budny MJ, Chiellini G, Cunha-Lima ST, Togashi M, Webb P, Baxter JD, Scanlan TS, Fletterick RJ. Proc Natl Acad Sci U S A 100 15358-15363 (2003)
  2. Halogen bonding in ligand-receptor systems in the framework of classical force fields. Rendine S, Pieraccini S, Forni A, Sironi M. Phys Chem Chem Phys 13 19508-19516 (2011)
  3. Structural basis for negative cooperativity within agonist-bound TR:RXR heterodimers. Putcha BD, Wright E, Brunzelle JS, Fernandez EJ. Proc Natl Acad Sci U S A 109 6084-6087 (2012)
  4. Endocrine and neuropsychological assessment in a child with a novel mutation of thyroid hormone receptor: response to 12-month triiodothyroacetic acid (TRIAC) therapy. Torre P, Bertoli M, Di Giovanni S, Scommegna S, Conte C, Novelli G, Cianfarani S. J Endocrinol Invest 28 657-662 (2005)
  5. Design and synthesis of complementing ligands for mutant thyroid hormone receptor TRbeta(R320H): a tailor-made approach toward the treatment of resistance to thyroid hormone. Hashimoto A, Shi Y, Drake K, Koh JT. Bioorg Med Chem 13 3627-3639 (2005)
  6. Local motifs involved in the canonical structure of the ligand-binding domain in the nuclear receptor superfamily. Tsuji M. J Struct Biol 185 355-365 (2014)
  7. Differential effects of TR ligands on hormone dissociation rates: evidence for multiple ligand entry/exit pathways. Cunha Lima ST, Nguyen NH, Togashi M, Apriletti JW, Nguyen P, Polikarpov I, Scanlan TS, Baxter JD, Webb P. J Steroid Biochem Mol Biol 117 125-131 (2009)
  8. Recognition of fold- and function-specific sites in the ligand-binding domain of the thyroid hormone receptor-like family. Verma S, Chakraborti S, Singh OP, Pande V, Dixit R, Pandey AV, Pandey KC. Front Endocrinol (Lausanne) 13 981090 (2022)
  9. Thyroid Hormone Resistance in Identical Twin Sisters with Atrial Fibrillation: Case Report and Review of the Literature. Zimering MB. J Endocrinol Diabetes 5 (2018)


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