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Structural basis of GC-1 selectivity for thyroid hormone receptor isoforms.

Bleicher L, Aparicio R, Nunes FM, Martinez L, Gomes Dias SM, Figueira AC, Santos MA, Venturelli WH, da Silva R, Donate PM, Neves FA, Simeoni LA, Baxter JD, Webb P, Skaf MS, Polikarpov I
BMC Struct Biol 8 8 (2008)
Related entries: 3hzf, 3ilz

Cited: 26 times
EuropePMC logo PMID: 18237438

Abstract

Background

Thyroid receptors, TRalpha and TRbeta, are involved in important physiological functions such as metabolism, cholesterol level and heart activities. Whereas metabolism increase and cholesterol level lowering could be achieved by TRbeta isoform activation, TRalpha activation affects heart rates. Therefore, beta-selective thyromimetics have been developed as promising drug-candidates for treatment of obesity and elevated cholesterol level. GC-1 [3,5-dimethyl-4-(4'-hydroxy-3'-isopropylbenzyl)-phenoxy acetic acid] has ability to lower LDL cholesterol with 600- to 1400-fold more potency and approximately two- to threefold more efficacy than atorvastatin (Lipitor(c)) in studies in rats, mice and monkeys.

Results

To investigate GC-1 specificity, we solved crystal structures and performed molecular dynamics simulations of both isoforms complexed with GC-1. Crystal structures reveal that, in TRalpha Arg228 is observed in multiple conformations, an effect triggered by the differences in the interactions between GC-1 and Ser277 or the corresponding asparagine (Asn331) of TRbeta. The corresponding Arg282 of TRbeta is observed in only one single stable conformation, interacting effectively with the ligand. Molecular dynamics support this model: our simulations show that the multiple conformations can be observed for the Arg228 in TRalpha, in which the ligand interacts either strongly with the ligand or with the Ser277 residue. In contrast, a single stable Arg282 conformation is observed for TRbeta, in which it strongly interacts with both GC-1 and the Asn331.

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  2. How the Structure of Per- and Polyfluoroalkyl Substances (PFAS) Influences Their Binding Potency to the Peroxisome Proliferator-Activated and Thyroid Hormone Receptors-An In Silico Screening Study. Kowalska D, Sosnowska A, Bulawska N, Stępnik M, Besselink H, Behnisch P, Puzyn T. Molecules 28 479 (2023)


Reviews citing this publication (12)

  1. Structural overview of the nuclear receptor superfamily: insights into physiology and therapeutics. Huang P, Chandra V, Rastinejad F. Annu Rev Physiol 72 247-272 (2010)
  2. High-throughput crystallography for structural genomics. Joachimiak A. Curr Opin Struct Biol 19 573-584 (2009)
  3. Anti-Obesity Therapy: from Rainbow Pills to Polyagonists. Müller TD, Clemmensen C, Finan B, DiMarchi RD, Tschöp MH. Pharmacol Rev 70 712-746 (2018)
  4. Selective Thyroid Hormone Receptor-Beta (TRβ) Agonists: New Perspectives for the Treatment of Metabolic and Neurodegenerative Disorders. Saponaro F, Sestito S, Runfola M, Rapposelli S, Chiellini G. Front Med (Lausanne) 7 331 (2020)
  5. Thyromimetics: a journey from bench to bed-side. Tancevski I, Rudling M, Eller P. Pharmacol Ther 131 33-39 (2011)
  6. Thiazolidine-2,4-dione derivatives: programmed chemical weapons for key protein targets of various pathological conditions. Chadha N, Bahia MS, Kaur M, Silakari O. Bioorg Med Chem 23 2953-2974 (2015)
  7. Evolution of ligands, receptors and metabolizing enzymes of thyroid signaling. Holzer G, Roux N, Laudet V. Mol Cell Endocrinol 459 5-13 (2017)
  8. Cross-talk between the thyroid and liver: a new target for nonalcoholic fatty liver disease treatment. Huang YY, Gusdon AM, Qu S. World J Gastroenterol 19 8238-8246 (2013)
  9. Thyroid hormone analogues: where do we stand in 2013? Meruvu S, Ayers SD, Winnier G, Webb P. Thyroid 23 1333-1344 (2013)
  10. GC-1: A Thyromimetic With Multiple Therapeutic Applications in Liver Disease. Columbano A, Chiellini G, Kowalik MA. Gene Expr 17 265-275 (2017)
  11. Thyromimetics: a review of recent reports and patents (2004 - 2009). Hirano T, Kagechika H. Expert Opin Ther Pat 20 213-228 (2010)
  12. International Union of Basic and Clinical Pharmacology CXIII: Nuclear Receptor Superfamily-Update 2023. Burris TP, de Vera IMS, Cote I, Flaveny CA, Wanninayake US, Chatterjee A, Walker JK, Steinauer N, Zhang J, Coons LA, Korach KS, Cain DW, Hollenberg AN, Webb P, Forrest D, Jetten AM, Edwards DP, Grimm SL, Hartig S, Lange CA, Richer JK, Sartorius CA, Tetel M, Billon C, Elgendy B, Hegazy L, Griffett K, Peinetti N, Burnstein KL, Hughes TS, Sitaula S, Stayrook KR, Culver A, Murray MH, Finck BN, Cidlowski JA. Pharmacol Rev 75 1233-1318 (2023)

Articles citing this publication (12)

  1. Gaining ligand selectivity in thyroid hormone receptors via entropy. Martínez L, Nascimento AS, Nunes FM, Phillips K, Aparicio R, Dias SM, Figueira AC, Lin JH, Nguyen P, Apriletti JW, Neves FA, Baxter JD, Webb P, Skaf MS, Polikarpov I. Proc Natl Acad Sci U S A 106 20717-20722 (2009)
  2. Molecular mechanism of peroxisome proliferator-activated receptor α activation by WY14643: a new mode of ligand recognition and receptor stabilization. Bernardes A, Souza PC, Muniz JR, Ricci CG, Ayers SD, Parekh NM, Godoy AS, Trivella DB, Reinach P, Webb P, Skaf MS, Polikarpov I. J Mol Biol 425 2878-2893 (2013)
  3. Structure and dynamics of the second CARD of human RIG-I provide mechanistic insights into regulation of RIG-I activation. Ferrage F, Dutta K, Nistal-Villán E, Patel JR, Sánchez-Aparicio MT, De Ioannes P, Buku A, Aseguinolaza GG, García-Sastre A, Aggarwal AK. Structure 20 2048-2061 (2012)
  4. Identification of a new hormone-binding site on the surface of thyroid hormone receptor. Souza PC, Puhl AC, Martínez L, Aparício R, Nascimento AS, Figueira AC, Nguyen P, Webb P, Skaf MS, Polikarpov I. Mol Endocrinol 28 534-545 (2014)
  5. Revealing a Mutant-Induced Receptor Allosteric Mechanism for the Thyroid Hormone Resistance. Yao B, Wei Y, Zhang S, Tian S, Xu S, Wang R, Zheng W, Li Y. iScience 20 489-496 (2019)
  6. Site-specific basicities regulate molecular recognition in receptor binding: in silico docking of thyroid hormones. Tóth G, Baska F, Schretner A, Rácz A, Noszál B. Eur Biophys J 42 721-730 (2013)
  7. Structural modeling of high-affinity thyroid receptor-ligand complexes. de Araujo AS, Martínez L, de Paula Nicoluci R, Skaf MS, Polikarpov I. Eur Biophys J 39 1523-1536 (2010)
  8. Bacterial biosensors for screening isoform-selective ligands for human thyroid receptors α-1 and β-1. Gierach I, Li J, Wu WY, Grover GJ, Wood DW. FEBS Open Bio 2 247-253 (2012)
  9. The Affinity of Brominated Phenolic Compounds for Human and Zebrafish Thyroid Receptor β: Influence of Chemical Structure. Kollitz EM, De Carbonnel L, Stapleton HM, Lee Ferguson P. Toxicol Sci 163 226-239 (2018)
  10. Quantification of Thyromimetic Sobetirome Concentration in Biological Tissue Samples. Devereaux J, Ferrara SJ, Scanlan TS. Methods Mol Biol 1801 193-206 (2018)
  11. TRβ Agonism Induces Tumor Suppression and Enhances Drug Efficacy in Anaplastic Thyroid Cancer in Female Mice. Gillis NE, Cozzens LM, Wilson ER, Smith NM, Tomczak JA, Bolf EL, Carr FE. Endocrinology 164 bqad135 (2023)
  12. Structural insights revealed by two novel THRB mutations. Cardoso LF, de Carvalho Melo MC, Takahashi MH, Nascimento AS, Chiamolera MI, Maciel LMZ. Endocrine 68 241-247 (2020)


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