PDBsum entry 1nav

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Membrane protein PDB id
Protein chain
253 a.a. *
Waters ×28
* Residue conservation analysis
PDB id:
Name: Membrane protein
Title: Thyroid receptor alpha in complex with an agonist selective thyroid receptor beta1
Structure: Hormone receptor alpha 1, thra1. Chain: a. Fragment: ligand binding domain (residues 148-408). Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
2.50Å     R-factor:   0.246     R-free:   0.279
Authors: L.Ye,Y.L.Li,K.Mellstrom,C.Mellin,L.G.Bladh,K.Koehler,N.Garg, A.M.Garcia Collazo,C.Litten,B.Husman,K.Persson,J.Ljunggren, P.G.Sleph,R.George,J.Malm
Key ref: L.Ye et al. (2003). Thyroid receptor ligands. 1. Agonist ligands selective for the thyroid receptor beta1. J Med Chem, 46, 1580-1588. PubMed id: 12699376 DOI: 10.1021/jm021080f
29-Nov-02     Release date:   17-Jun-03    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P10827  (THA_HUMAN) -  Thyroid hormone receptor alpha
490 a.a.
253 a.a.*
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 39 residue positions (black crosses)

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     nucleus   1 term 
  Biological process     steroid hormone mediated signaling pathway   2 terms 
  Biochemical function     DNA binding     4 terms  


DOI no: 10.1021/jm021080f J Med Chem 46:1580-1588 (2003)
PubMed id: 12699376  
Thyroid receptor ligands. 1. Agonist ligands selective for the thyroid receptor beta1.
L.Ye, Y.L.Li, K.Mellström, C.Mellin, L.G.Bladh, K.Koehler, N.Garg, A.M.Garcia Collazo, C.Litten, B.Husman, K.Persson, J.Ljunggren, G.Grover, P.G.Sleph, R.George, J.Malm.
Endogenous thyroid receptor hormones 3,5,3',5'-tetraiodo-l-thyronine (T(4), 1) and 3,5,3'-triiodo-l-thyronine (T(3), 2) exert a significant effects on growth, development, and homeostasis in mammals. They regulate important genes in intestinal, skeletal, and cardiac muscles, the liver, and the central nervous system, influence overall metabolic rate, cholesterol and triglyceride levels, and heart rate, and affect mood and overall sense of well being. The literature suggests many or most effects of thyroid hormones on the heart, in particular on the heart rate and rhythm, are mediated through the TRalpha(1) isoform, while most actions of the hormones on the liver and other tissues are mediated more through the TRbeta(1) isoform of the receptor. Some effects of thyroid hormones may be therapeutically useful in nonthyroid disorders if adverse effects can be minimized or eliminated. These potentially useful features include weight reduction for the treatment of obesity, cholesterol lowering for treating hyperlipidemia, amelioration of depression, and stimulation of bone formation in osteoporosis. Prior attempts to utilize thyroid hormones pharmacologically to treat these disorders have been limited by manifestations of hyperthyroidism and, in particular, cardiovascular toxicity. Consequently, development of thyroid hormone receptor agonists that are selective for the beta-isoform could lead to safe therapies for these common disorders while avoiding cardiotoxicity. We describe here the synthesis and evaluation of a series of novel TR ligands, which are selective for TRbeta(1) over TRalpha(1). These ligands could potentially be useful for treatment of various disorders as outlined above. From a series of homologous R(1)-substituted carboxylic acid derivatives, increasing chain length was found to have a profound effect on affinity and selectivity in a radioreceptor binding assay for the human thyroid hormone receptors alpha(1) and beta(1) (TRalpha(1) and TRbeta(2)) as well as a reporter cell assay employing CHOK1-cells (Chinese hamster ovary cells) stably transfected with hTRalpha(1) or hTRbeta(1) and an alkaline phosphatase reporter-gene downstream thyroid response element (TRAFalpha(1) and TRAFbeta(1)). Affinity increases in the order formic, acetic, and propionic acid, while beta-selectivity is highest when the R(1) position is substituted with acetic acid. Within this series 3,5-dibromo-4-[(4-hydroxy-3-isopropylphenoxy)phenyl]acetic acid (11a) and 3,5-dichloro-4-[(4-hydroxy-3-isopropylphenoxy)phenyl]acetic acid (15) were found to reveal the most promising in vitro data based on isoform selectivity and were selected for further in vivo studies. The effect of 2, 11a, and 15 in a cholesterol-fed rat model was monitored including potencies for heart rate (ED(15)), cholesterol (ED(50)), and TSH (ED(50)). Potency for tachycardia was significantly reduced for the TRbeta selective compounds 11a and 15 compared with 2, while both 11a and 15 retained the cholesterol-lowering potency of 2. This left an approximately 10-fold therapeutic window between heart rate and cholesterol, which is consistent with the action of ligands that are approximately 10-fold more selective for TRbeta(1). We also report the X-ray crystallographic structures of the ligand binding domains of TRalpha and TRbeta in complex with 15. These structures reveal that the single amino acid difference in the ligand binding pocket (Ser277 in TRalpha or Asn331 in TRbeta) results in a slightly different hydrogen bonding pattern that may explain the increased beta-selectivity of 15.

Literature references that cite this PDB file's key reference

  PubMed id Reference
20512645 Araujo, L.Martínez, Paula Nicoluci, M.S.Skaf, and I.Polikarpov (2010).
Structural modeling of high-affinity thyroid receptor-ligand complexes.
  Eur Biophys J, 39, 1523-1536.  
19337272 J.D.Baxter, and P.Webb (2009).
Thyroid hormone mimetics: potential applications in atherosclerosis, obesity and type 2 diabetes.
  Nat Rev Drug Discov, 8, 308-320.  
19926848 L.Martínez, A.S.Nascimento, F.M.Nunes, K.Phillips, R.Aparicio, S.M.Dias, A.C.Figueira, J.H.Lin, P.Nguyen, J.W.Apriletti, F.A.Neves, J.D.Baxter, P.Webb, M.S.Skaf, and I.Polikarpov (2009).
Gaining ligand selectivity in thyroid hormone receptors via entropy.
  Proc Natl Acad Sci U S A, 106, 20717-20722.
PDB codes: 3jzb 3jzc
18297677 K.Takamatsu, A.Takano, N.Yakushiji, K.Morohashi, K.Morishita, N.Matsuura, M.Makishima, A.Tai, K.Sasaki, and H.Kakuta (2008).
The first potent subtype-selective retinoid X receptor (RXR) agonist possessing a 3-isopropoxy-4-isopropylphenylamino moiety, NEt-3IP (RXRalpha/beta-dual agonist).
  ChemMedChem, 3, 780-787.  
18237438 L.Bleicher, R.Aparicio, F.M.Nunes, L.Martinez, S.M.Gomes Dias, A.C.Figueira, M.A.Santos, W.H.Venturelli, R.da Silva, P.M.Donate, F.A.Neves, L.A.Simeoni, J.D.Baxter, P.Webb, M.S.Skaf, and I.Polikarpov (2008).
Structural basis of GC-1 selectivity for thyroid hormone receptor isoforms.
  BMC Struct Biol, 8, 8.
PDB codes: 3hzf 3ilz 3imy
18279024 M.Moreno, Lange, A.Lombardi, E.Silvestri, A.Lanni, and F.Goglia (2008).
Metabolic effects of thyroid hormone derivatives.
  Thyroid, 18, 239-253.  
17096449 A.Vedani, M.Zumstein, M.A.Lill, and B.Ernst (2007).
Simulating alpha/beta Selectivity at the Human Thyroid Hormone Receptor: Consensus Scoring Using Multidimensional QSAR.
  ChemMedChem, 2, 78-87.  
17696568 B.Drolet, C.Simard, and P.Poirier (2007).
Impact of weight-loss medications on the cardiovascular system: focus on current and future anti-obesity drugs.
  Am J Cardiovasc Drugs, 7, 273-288.  
17524652 H.Liu, and P.Gramatica (2007).
QSAR study of selective ligands for the thyroid hormone receptor beta.
  Bioorg Med Chem, 15, 5251-5261.  
17615682 K.K.Jung, S.Y.Kim, T.G.Kim, J.H.Kang, S.Y.Kang, J.Y.Cho, and S.H.Kim (2007).
Differential regulation of thyroid hormone receptor-mediated function by endocrine disruptors.
  Arch Pharm Res, 30, 616-623.  
17878314 M.D.Erion, E.E.Cable, B.R.Ito, H.Jiang, J.M.Fujitaki, P.D.Finn, B.H.Zhang, J.Hou, S.H.Boyer, P.D.van Poelje, and D.L.Linemeyer (2007).
Targeting thyroid hormone receptor-beta agonists to the liver reduces cholesterol and triglycerides and improves the therapeutic index.
  Proc Natl Acad Sci U S A, 104, 15490-15495.  
16930291 A.Vedani, M.Dobler, and M.A.Lill (2006).
The challenge of predicting drug toxicity in silico.
  Basic Clin Pharmacol Toxicol, 99, 195-208.  
16007230 G.J.Grover, K.Mellstrom, and J.Malm (2005).
Development of the thyroid hormone receptor beta-subtype agonist KB-141: a strategy for body weight reduction and lipid lowering with minimal cardiac side effects.
  Cardiovasc Drug Rev, 23, 133-148.  
16263725 L.A.Arnold, E.Estébanez-Perpiñá, M.Togashi, N.Jouravel, A.Shelat, A.C.McReynolds, E.Mar, P.Nguyen, J.D.Baxter, R.J.Fletterick, P.Webb, and R.K.Guy (2005).
Discovery of small molecule inhibitors of the interaction of the thyroid hormone receptor with transcriptional coregulators.
  J Biol Chem, 280, 43048-43055.  
15699348 L.E.Macdonald, K.E.Wortley, L.C.Gowen, K.D.Anderson, J.D.Murray, W.T.Poueymirou, M.V.Simmons, D.Barber, D.M.Valenzuela, A.N.Economides, S.J.Wiegand, G.D.Yancopoulos, M.W.Sleeman, and A.J.Murphy (2005).
Resistance to diet-induced obesity in mice globally overexpressing OGH/GPB5.
  Proc Natl Acad Sci U S A, 102, 2496-2501.  
15980170 L.Martínez, M.T.Sonoda, P.Webb, J.D.Baxter, M.S.Skaf, and I.Polikarpov (2005).
Molecular dynamics simulations reveal multiple pathways of ligand dissociation from thyroid hormone receptors.
  Biophys J, 89, 2011-2023.  
15466465 B.Sandler, P.Webb, J.W.Apriletti, B.R.Huber, M.Togashi, S.T.Cunha Lima, S.Juric, S.Nilsson, R.Wagner, R.J.Fletterick, and J.D.Baxter (2004).
Thyroxine-thyroid hormone receptor interactions.
  J Biol Chem, 279, 55801-55808.
PDB codes: 1xzx 1y0x
15388935 F.M.Nunes, R.Aparicio, M.A.Santos, R.V.Portugal, S.M.Dias, F.A.Neves, L.A.Simeoni, J.D.Baxter, P.Webb, and I.Polikarpov (2004).
Crystallization and preliminary X-ray diffraction studies of isoform alpha1 of the human thyroid hormone receptor ligand-binding domain.
  Acta Crystallogr D Biol Crystallogr, 60, 1867-1870.  
15109613 J.D.Baxter, P.Webb, G.Grover, and T.S.Scanlan (2004).
Selective activation of thyroid hormone signaling pathways by GC-1: a new approach to controlling cholesterol and body weight.
  Trends Endocrinol Metab, 15, 154-157.  
15610734 L.Shan, J.Vincent, J.S.Brunzelle, I.Dussault, M.Lin, I.Ianculescu, M.A.Sherman, B.M.Forman, and E.J.Fernandez (2004).
Structure of the murine constitutive androstane receptor complexed to androstenol: a molecular basis for inverse agonism.
  Mol Cell, 16, 907-917.
PDB code: 1xnx
12888625 G.J.Grover, K.Mellström, L.Ye, J.Malm, Y.L.Li, L.G.Bladh, P.G.Sleph, M.A.Smith, R.George, B.Vennström, K.Mookhtiar, R.Horvath, J.Speelman, D.Egan, and J.D.Baxter (2003).
Selective thyroid hormone receptor-beta activation: a strategy for reduction of weight, cholesterol, and lipoprotein (a) with reduced cardiovascular liability.
  Proc Natl Acad Sci U S A, 100, 10067-10072.  
14696916 M.Murata, K.Yano, S.Kuroki, T.Suzutani, and Y.Katayama (2003).
Protein-immobilized electrode for rapid and convenient sensing of thyroid hormone receptor-ligand interaction.
  Anal Sci, 19, 1569-1573.  
14673100 S.Borngraeber, M.J.Budny, G.Chiellini, S.T.Cunha-Lima, M.Togashi, P.Webb, J.D.Baxter, T.S.Scanlan, and R.J.Fletterick (2003).
Ligand selectivity by seeking hydrophobicity in thyroid hormone receptor.
  Proc Natl Acad Sci U S A, 100, 15358-15363.
PDB code: 1q4x
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.