spacer
spacer

PDBsum entry 1q4x
Go to PDB code: 
protein ligands links
Transcription PDB id
1q4x

 

 

 

 

Loading ...

 
JSmol PyMol  
Contents
Protein chain
239 a.a. *
Ligands
G24 ×2
Waters ×40
* Residue conservation analysis
PDB id:
1q4x
Name: Transcription
Title: Crystal structure of human thyroid hormone receptor beta lbd in complex with specific agonist gc-24
Structure: Thyroid hormone receptor beta-1. Chain: a. Fragment: ligand binding domain. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: thrb or nr1a2 or erba2 or thr1. Expressed in: escherichia coli bl21. Expression_system_taxid: 511693.
Resolution:
2.80Å     R-factor:   0.216     R-free:   0.264
Authors: S.Borngraeber,M.J.Budny,G.Chiellini,S.T.Cunha-Lima,M.Togashi,P.Webb, J.D.Baxter,T.S.Scanlan,R.J.Fletterick
Key ref:
S.Borngraeber et al. (2003). Ligand selectivity by seeking hydrophobicity in thyroid hormone receptor. Proc Natl Acad Sci U S A, 100, 15358-15363. PubMed id: 14673100 DOI: 10.1073/pnas.2136689100
Date:
04-Aug-03     Release date:   03-Feb-04    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
P10828  (THB_HUMAN) -  Thyroid hormone receptor beta from Homo sapiens
Seq:
Struc: 		461 a.a.
239 a.a.
Key:    Secondary structure  CATH domain

 

 
DOI no: 10.1073/pnas.2136689100 Proc Natl Acad Sci U S A 100:15358-15363 (2003)
PubMed id: 14673100  
 
 
Ligand selectivity by seeking hydrophobicity in thyroid hormone receptor.
S.Borngraeber, M.J.Budny, G.Chiellini, S.T.Cunha-Lima, M.Togashi, P.Webb, J.D.Baxter, T.S.Scanlan, R.J.Fletterick.
 
  ABSTRACT  
 
Selective therapeutics for nuclear receptors would revolutionize treatment for endocrine disease. Specific control of nuclear receptor activity is challenging because the internal cavities that bind hormones can be virtually identical. Only one highly selective hormone analog is known for the thyroid receptor, GC-24, an agonist for human thyroid hormone receptor beta. The compound differs from natural hormone in benzyl, substituting for an iodine atom in the 3' position. The benzyl is too large to fit into the enclosed pocket of the receptor. The crystal structure of human thyroid hormone receptor beta at 2.8-A resolution with GC-24 bound explains its agonist activity and unique isoform specificity. The benzyl of GC-24 is accommodated through shifts of 3-4 A in two helices. These helices are required for binding hormone and positioning the critical helix 12 at the C terminus. Despite these changes, the complex associates with coactivator as tightly as human thyroid hormone receptor bound to thyroid hormone and is fully active. Our data suggest that increased specificity of ligand recognition derives from creating a new hydrophobic cluster with ligand and protein components.
 
  Selected figure(s)  
 
Figure 1.
Fig. 1. Chemical formulas for TR modulators. (a) GC-24. (b) GC-1. (c) Thyroid hormone (T[3]). 		Figure 6.
Fig. 6. The environment of the hydrophobic benzyl extension of GC-24. GC-24 and surrounding side chains are shown in beige, and GC-1 is shown in blue. (a) Residues most changed by GC-24 binding are found at the start of helix 3 and the C terminus of helix 11. (b) Phe-451, Pro-452, Phe-455, and, to a lesser extent, Ile-276 (residue not shown) enhance the hydrophobic cluster linking helix 11 and helix 12 to the receptor core only in GC-24. The benzyl participates in close packing interactions with six hydrophobic side chains.
 
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20512645 A.S.de Araujo, L.Martínez, R.de Paula Nicoluci, M.S.Skaf, and I.Polikarpov (2010).
Structural modeling of high-affinity thyroid receptor-ligand complexes.
  Eur Biophys J, 39, 1523-1536.  
20148675 P.Huang, V.Chandra, and F.Rastinejad (2010).
Structural overview of the nuclear receptor superfamily: insights into physiology and therapeutics.
  Annu Rev Physiol, 72, 247-272.  
19002578 T.S.Scanlan (2010).
Sobetirome: a case history of bench-to-clinic drug discovery and development.
  Heart Fail Rev, 15, 177-182.  
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
18798561 N.Jouravel, E.Sablin, M.Togashi, J.D.Baxter, P.Webb, and R.J.Fletterick (2009).
Molecular basis for dimer formation of TRbeta variant D355R.
  Proteins, 75, 111-117.
PDB code: 3d57
19729063 S.T.Cunha Lima, N.H.Nguyen, M.Togashi, J.W.Apriletti, P.Nguyen, I.Polikarpov, T.S.Scanlan, J.D.Baxter, and P.Webb (2009).
Differential effects of TR ligands on hormone dissociation rates: evidence for multiple ligand entry/exit pathways.
  J Steroid Biochem Mol Biol, 117, 125-131.  
18160712 K.Suino-Powell, Y.Xu, C.Zhang, Y.G.Tao, W.D.Tolbert, S.S.Simons, and H.E.Xu (2008).
Doubling the size of the glucocorticoid receptor ligand binding pocket by deacylcortivazol.
  Mol Cell Biol, 28, 1915-1923.
PDB code: 3bqd
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
18279020 M.O.Ribeiro (2008).
Effects of thyroid hormone analogs on lipid metabolism and thermogenesis.
  Thyroid, 18, 197-203.  
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
17311914 C.E.Bohl, Z.Wu, D.D.Miller, C.E.Bell, and J.T.Dalton (2007).
Crystal structure of the T877A human androgen receptor ligand-binding domain complexed to cyproterone acetate provides insight for ligand-induced conformational changes and structure-based drug design.
  J Biol Chem, 282, 13648-13655.
PDB code: 2oz7
17911242 E.Estébanez-Perpiñá, L.A.Arnold, A.A.Arnold, P.Nguyen, E.D.Rodrigues, E.Mar, R.Bateman, P.Pallai, K.M.Shokat, J.D.Baxter, R.K.Guy, P.Webb, and R.J.Fletterick (2007).
A surface on the androgen receptor that allosterically regulates coactivator binding.
  Proc Natl Acad Sci U S A, 104, 16074-16079.
PDB codes: 2pio 2pip 2piq 2pir 2pit 2piu 2piv 2piw 2pix 2pkl 2qpy
15947969 E.H.Miyabara, M.S.Aoki, A.G.Soares, R.M.Saltao, C.M.Vilicev, M.Passarelli, T.S.Scanlan, C.H.Gouveia, and A.S.Moriscot (2005).
Thyroid hormone receptor-beta-selective agonist GC-24 spares skeletal muscle type I to II fiber shift.
  Cell Tissue Res, 321, 233-241.  
15709961 K.W.Nettles, and G.L.Greene (2005).
Ligand control of coregulator recruitment to nuclear receptors.
  Annu Rev Physiol, 67, 309-333.  
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.  
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.

 

spacer
spacer