1nq0: Difference between revisions

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OCA

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-[[Image:1nq0.gif|left|200px]]<br />
-<applet load="1nq0" size="450" color="white" frame="true" align="right" spinBox="true"
-caption="1nq0, resolution 2.40&Aring;" />
-'''TR Receptor Mutations Conferring Hormone Resistance and Reduced Corepressor Release Exhibit Decreased Stability in the Nterminal LBD'''<br />
-==Overview==
+==TR Receptor Mutations Conferring Hormone Resistance and Reduced Corepressor Release Exhibit Decreased Stability in the Nterminal LBD==
-Resistance to thyroid hormone (RTH) syndrome is associated with mutations, in the human thyroid hormone receptor-beta (hTRbeta), many of which show, marked reduction in hormone binding. Here, we investigated the structural, consequences of two RTH mutants (A234T and R243Q), residing in the, flexible N-terminal portion of the ligand binding domain (LBD), which, exhibit modestly reduced hormone binding with impaired release of, corepressor. X-ray crystallography analyses revealed that these two RTH, mutants modulate the position of this flexible region by either altering, the movement of helix 1 (A234T) or disrupting a salt bridge (R243Q). The, subsequent increased flexibility and mobility in regions after the two, sites of mutation coincided with a disorganized LBD. Consistent with this, finding, the ability of these mutant N-terminal regions (234-260) to, recruit the remaining LBD was decreased in a ligand-dependent helix, assembly assay. Collectively, these data suggest that structural, information imparted by the flexible segment in the N-terminal LBD is, critical for overall stability of the LBD. Thus, these structural analyses, provide mechanistic insight into the etiology of RTH disease in human, TRbeta mutants that exhibit hormone binding with decreased, ligand-dependent corepressor release.
+<StructureSection load='1nq0' size='340' side='right'caption='[[1nq0]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[1nq0]] 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=1NQ0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1NQ0 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]] 2.4&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4HY:[4-(4-HYDROXY-3-IODO-PHENOXY)-3,5-DIIODO-PHENYL]-ACETIC+ACID'>4HY</scene>, <scene name='pdbligand=ARS:ARSENIC'>ARS</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=1nq0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1nq0 OCA], [https://pdbe.org/1nq0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1nq0 RCSB], [https://www.ebi.ac.uk/pdbsum/1nq0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1nq0 ProSAT]</span></td></tr>
+</table>
+== Disease ==
+[https://www.uniprot.org/uniprot/THB_HUMAN THB_HUMAN] Defects in THRB are the cause of generalized thyroid hormone resistance (GTHR) [MIM:[https://omim.org/entry/188570 188570]. GTHR is a disease characterized by goiter, abnormal mental functions, increased susceptibility to infections, abnormal growth and bone maturation, tachycardia and deafness. Affected individuals may also have attention deficit-hyperactivity disorders (ADHD) and language difficulties. GTHR patients also have high levels of circulating thyroid hormones (T3-T4), with normal or slightly elevated thyroid stimulating hormone (TSH).<ref>PMID:2510172</ref> <ref>PMID:2153155</ref> <ref>PMID:1846005</ref> <ref>PMID:1661299</ref> <ref>PMID:1653889</ref> <ref>PMID:1563081</ref> <ref>PMID:1314846</ref> <ref>PMID:1619012</ref> <ref>PMID:1587388</ref> <ref>PMID:1324420</ref> <ref>PMID:8514853</ref> <ref>PMID:8175986</ref> <ref>PMID:7833659</ref> <ref>PMID:8664910</ref> <ref>PMID:8889584</ref> <ref>PMID:10660344</ref> <ref>PMID:16804041</ref> <ref>PMID:19268523</ref>   Defects in THRB are the cause of generalized thyroid hormone resistance autosomal recessive (GTHRAR) [MIM:[https://omim.org/entry/274300 274300]. An autosomal recessive disorder characterized by goiter, clinical euthyroidism, end-organ unresponsiveness to thyroid hormone, abnormal growth and bone maturation, and deafness. Patients also have high levels of circulating thyroid hormones, with elevated thyroid stimulating hormone.  Defects in THRB are the cause of selective pituitary thyroid hormone resistance (PRTH) [MIM:[https://omim.org/entry/145650 145650]; also known as familial hyperthyroidism due to inappropriate thyrotropin secretion. PRTH is a variant form of thyroid hormone resistance and is characterized by clinical hyperthyroidism, with elevated free thyroid hormones, but inappropriately normal serum TSH. Unlike GRTH, where the syndrome usually segregates with a dominant allele, the mode of inheritance in PRTH has not been established.<ref>PMID:7528740</ref> <ref>PMID:8381821</ref>
+== Function ==
+[https://www.uniprot.org/uniprot/THB_HUMAN THB_HUMAN] High affinity receptor for triiodothyronine.<ref>PMID:17418816</ref>
+== Evolutionary Conservation ==
+[[Image:Consurf_key_small.gif|200px|right]]
+Check<jmol>
+  <jmolCheckbox>
+    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/nq/1nq0_consurf.spt"</scriptWhenChecked>
+    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
+    <text>to colour the structure by Evolutionary Conservation</text>
+  </jmolCheckbox>
+</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1nq0 ConSurf].
+<div style="clear:both"></div>
-==Disease==
+==See Also==
-Known diseases associated with this structure: Thyroid hormone resistance OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=190160 190160]], Thyroid hormone resistance, autosomal recessive OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=190160 190160]]
+*[[Thyroid hormone receptor 3D structures|Thyroid hormone receptor 3D structures]]
+== References ==
-==About this Structure==
+<references/>
-NQ0 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with 4HY and ARS as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1NQ0 OCA].
+__TOC__
+</StructureSection>
-==Reference==
-Thyroid hormone receptor-beta mutations conferring hormone resistance and reduced corepressor release exhibit decreased stability in the N-terminal ligand-binding domain., Huber BR, Desclozeaux M, West BL, Cunha-Lima ST, Nguyen HT, Baxter JD, Ingraham HA, Fletterick RJ, Mol Endocrinol. 2003 Jan;17(1):107-16. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=12511610 12511610]
 [[Category: Homo sapiens]]
-[[Category: Single protein]]
+[[Category: Large Structures]]
-[[Category: Baxter, J.D.]]
+[[Category: Baxter JD]]
-[[Category: Cunha-Lima, S.T.]]
+[[Category: Cunha-Lima ST]]
-[[Category: Desclozeaux, M.]]
+[[Category: Desclozeaux M]]
-[[Category: Fletterick, R.J.]]
+[[Category: Fletterick RJ]]
-[[Category: Huber, B.R.]]
+[[Category: Huber BR]]
-[[Category: Ingraham, H.A.]]
+[[Category: Ingraham HA]]
-[[Category: Nguyen, H.T.]]
+[[Category: Nguyen HT]]
-[[Category: West, B.L.]]
+[[Category: West BL]]
-[[Category: 4HY]]
-[[Category: ARS]]
-[[Category: thyroid hormone receptor]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 18:23:53 2007''