PDBsum entry 3gws

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Hormone activator PDB id
Protein chain
247 a.a. *
Waters ×175
* Residue conservation analysis
PDB id:
Name: Hormone activator
Title: Crystal structure of t3-bound thyroid hormone receptor
Structure: Thyroid hormone receptor beta. Chain: x. Fragment: ligand binding domain (unp residues 202 to 460). Synonym: nuclear receptor subfamily 1 group a member 2. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: thrb, erba2, nr1a2, thr1. Expressed in: escherichia coli. Expression_system_taxid: 562
2.20Å     R-factor:   0.193     R-free:   0.233
Authors: A.S.Nascimento,S.M.G.Dias,F.M.Nunes,R.Aparicio,I.Polikarpov, J.D.Baxter,P.Webb
Key ref:
A.S.Nascimento et al. (2006). Structural rearrangements in the thyroid hormone receptor hinge domain and their putative role in the receptor function. J Mol Biol, 360, 586-598. PubMed id: 16781732 DOI: 10.1016/j.jmb.2006.05.008
01-Apr-09     Release date:   28-Apr-09    
Supersedes: 2h6w
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P10828  (THB_HUMAN) -  Thyroid hormone receptor beta
461 a.a.
248 a.a.*
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 3 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: 10.1016/j.jmb.2006.05.008 J Mol Biol 360:586-598 (2006)
PubMed id: 16781732  
Structural rearrangements in the thyroid hormone receptor hinge domain and their putative role in the receptor function.
A.S.Nascimento, S.M.Dias, F.M.Nunes, R.Aparício, A.L.Ambrosio, L.Bleicher, A.C.Figueira, M.A.Santos, Oliveira Neto, H.Fischer, M.Togashi, A.F.Craievich, R.C.Garratt, J.D.Baxter, P.Webb, I.Polikarpov.
The thyroid hormone receptor (TR) D-domain links the ligand-binding domain (LBD, EF-domain) to the DNA-binding domain (DBD, C-domain), but its structure, and even its existence as a functional unit, are controversial. The D domain is poorly conserved throughout the nuclear receptor family and was originally proposed to comprise an unfolded hinge that facilitates rotation between the LBD and the DBD. Previous TR LBD structures, however, have indicated that the true unstructured region is three to six amino acid residues long and that the D-domain N terminus folds into a short amphipathic alpha-helix (H0) contiguous with the DBD and that the C terminus of the D-domain comprises H1 and H2 of the LBD. Here, we solve structures of TR-LBDs in different crystal forms and show that the N terminus of the TRalpha D-domain can adopt two structures; it can either fold into an amphipathic helix that resembles TRbeta H0 or form an unstructured loop. H0 formation requires contacts with the AF-2 coactivator-binding groove of the neighboring TR LBD, which binds H0 sequences that resemble coactivator LXXLL motifs. Structural analysis of a liganded TR LBD with small angle X-ray scattering (SAXS) suggests that AF-2/H0 interactions mediate dimerization of this protein in solution. We propose that the TR D-domain has the potential to form functionally important extensions of the DBD and LBD or unfold to permit TRs to adapt to different DNA response elements. We also show that mutations of the D domain LXXLL-like motif indeed selectively inhibit TR interactions with an inverted palindromic response element (F2) in vitro and TR activity at this response element in cell-based transfection experiments.
  Selected figure(s)  
Figure 1.
Figure 1. TR D domain CTE can adopt two structural forms: a structured α-helix (H0) and an unstructured peptide. (a) The hTRα structure in the orthorhombic space group with the D-domain CTE peptide folded as an α-helix. (Side-chains of the amino acid residues Met147 and Arg158 are in double conformation; only a preferred conformation is shown.) (b) The hTRβ structure with the D-domain CTE in the form of an α-helix. (c) Crystal structure of hTRα with the unfolded and unstructured hinge peptide (in the monoclinic space group).
Figure 3.
Figure 3. Superposition of the averaged SAXS DAMs (blue spheres) and the hinge-mediated crystallographic dimer of hTRα1 LBD shown as a cartoon in yellow and cyan. Three orthogonal stereo views are given.
  The above figures are reprinted by permission from Elsevier: J Mol Biol (2006, 360, 586-598) copyright 2006.  
  Figures were selected by the author.  

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.  
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
19141540 N.Nader, G.P.Chrousos, and T.Kino (2009).
Circadian rhythm transcription factor CLOCK regulates the transcriptional activity of the glucocorticoid receptor by acetylating its hinge region lysine cluster: potential physiological implications.
  FASEB J, 23, 1572-1583.  
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
18651760 M.D.Krasowski, E.J.Reschly, and S.Ekins (2008).
Intrinsic disorder in nuclear hormone receptors.
  J Proteome Res, 7, 4359-4372.  
18798693 S.W.Kruse, K.Suino-Powell, X.E.Zhou, J.E.Kretschman, R.Reynolds, C.Vonrhein, Y.Xu, L.Wang, S.Y.Tsai, M.J.Tsai, and H.E.Xu (2008).
Identification of COUP-TFII orphan nuclear receptor as a retinoic acid-activated receptor.
  PLoS Biol, 6, e227.
PDB code: 3cjw
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.