View source for 4lnw


==Crystal structure of TR-alpha bound to T3 in a second site==
<StructureSection load='4lnw' size='340' side='right'caption='[[4lnw]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4lnw]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4LNW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4LNW FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.9&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CAS:S-(DIMETHYLARSENIC)CYSTEINE'>CAS</scene>, <scene name='pdbligand=T3:3,5,3TRIIODOTHYRONINE'>T3</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4lnw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4lnw OCA], [https://pdbe.org/4lnw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4lnw RCSB], [https://www.ebi.ac.uk/pdbsum/4lnw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4lnw ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/THA_HUMAN THA_HUMAN] Defects in THRA are the cause of congenital hypothyroidism non-goitrous type 6 (CHNG6) [MIM:[https://omim.org/entry/614450 614450]. A disease characterized by growth retardation, developmental retardation, skeletal dysplasia, borderline low thyroxine levels and high triiodothyronine levels. There is differential sensitivity to thyroid hormone action, with retention of hormone responsiveness in the hypothalamic pituitary axis and liver but skeletal, gastrointestinal, and myocardial resistance.<ref>PMID:22168587</ref> 
== Function ==
[https://www.uniprot.org/uniprot/THA_HUMAN THA_HUMAN] Nuclear hormone receptor. High affinity receptor for triiodothyronine.
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Thyroid hormone receptors (TRs) are members of the nuclear receptor (NR) superfamily of ligand-activated transcription factors involved in cell differentiation, growth, and homeostasis. Although X-ray structures of many NR ligand binding domains (LBD) reveal that the ligand binds within the hydrophobic core of the ligand binding pocket (LBP), a few studies suggest the possibility of ligands bind to other sites. Here, we report a new x-ray crystallographic structure of TR-LBD that shows a second binding site for T3 and T4 located between H9, H10 and H11 of the TRalpha LBD surface. Statistical multiple sequence analysis, site-directed mutagenesis, and cell transactivation assays indicate that residues of the second binding site could be important for the TR function. We also conducted molecular dynamics (MD) simulations to investigate ligand mobility and ligand-protein interaction for T3 and T4 bound to this new TR surface binding site. Extensive MD simulations designed to compute ligand-protein dissociation constant indicate that the binding affinities to this surface site are of the order of the plasma and intracellular concentrations of the thyroid hormones, suggesting that ligands may bind to this new binding site under physiological conditions. Therefore, the second binding site could be useful as a new target site for drug design and could modulate selectively TR functions.

Identification of a NEW HORMONE binding site ON THE SURFACE of thyroid hormone receptor.,Souza PC, Puhl AC, Martinez L, Aparicio R, Nascimento AS, Figueira AC, Nguyen P, Webb P, Skaf MS, Polikarpov I Mol Endocrinol. 2014 Feb 19:me20131359. PMID:24552590<ref>PMID:24552590</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4lnw" style="background-color:#fffaf0;"></div>

==See Also==
*[[Thyroid hormone receptor|Thyroid hormone receptor]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Aparicio R]]
[[Category: Polikarpov I]]
[[Category: Puhl AC]]