View source for 7qdt


==Crystal structure of a mutant (P393GX) Thyroid Receptor Alpha ligand binding domain designed to model dominant negative human mutations.==
<StructureSection load='7qdt' size='340' side='right'caption='[[7qdt]], [[Resolution|resolution]] 3.00&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7qdt]] 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=7QDT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7QDT 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]] 3&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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=7qdt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7qdt OCA], [https://pdbe.org/7qdt PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7qdt RCSB], [https://www.ebi.ac.uk/pdbsum/7qdt PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7qdt 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.
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== Publication Abstract from PubMed ==
Mutations in thyroid hormone receptor alpha (TRalpha), a ligand-inducible transcription factor, cause Resistance to Thyroid Hormone alpha (RTHalpha). This disorder is characterised by tissue-specific hormone refractoriness and hypothyroidism, due to inhibition of target gene expression by mutant TRalpha-corepressor complexes. Using biophysical approaches, we show that RTHalpha-associated TRalpha mutants devoid of ligand-dependent transcription activation function, unexpectedly retain the ability to bind thyroid hormone. Visualisation of ligand (T3) within the crystal structure of a prototypic TRalpha mutant, validates this notion. This finding prompted synthesis of different thyroid hormone analogues, identifying a lead compound (ES08) which dissociates corepressor from mutant human TRalpha more efficaciously than T3. ES08 rescues developmental anomalies in a zebrafish model of RTHalpha and induces target gene expression in TRalpha mutation-containing cells from an RTHalpha patient, more effectively than T3. Our observations provide proof-of-principle for developing synthetic ligands that can relieve transcriptional repression by the mutant TRalpha-corepressor complex, for treatment of RTHalpha.

Structure-guided approach to relieving transcriptional repression inResistance to Thyroid Hormone alpha.,Romartinez-Alonso B, Agostini M, Jones H, McLellan J, Sood D, Tomkinson N, Marelli F, Gentile I, Visser WE, Schoenmakers E, Fairall L, Privalsky M, Moran C, Persani L, Chatterjee K, Schwabe J Mol Cell Biol. 2021 Dec 6:MCB0036321. doi: 10.1128/MCB.00363-21. PMID:34871063<ref>PMID:34871063</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 7qdt" style="background-color:#fffaf0;"></div>

==See Also==
*[[Thyroid hormone receptor 3D structures|Thyroid hormone receptor 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Agostini M]]
[[Category: Chatterjee K]]
[[Category: Fairall L]]
[[Category: Romartinez-Alonso B]]
[[Category: Schwabe J]]