4zo1
From Proteopedia
(Difference between revisions)
| Line 1: | Line 1: | ||
| - | ''' | + | ==Crystal Structure of the T3-bound TR-beta Ligand-binding Domain in complex with RXR-alpha== |
| + | <StructureSection load='4zo1' size='340' side='right' caption='[[4zo1]], [[Resolution|resolution]] 3.22Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[4zo1]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/ ] and [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4ZO1 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ZO1 FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4zo1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zo1 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4zo1 RCSB], [http://www.ebi.ac.uk/pdbsum/4zo1 PDBsum]</span></td></tr> | ||
| + | </table> | ||
| + | == Disease == | ||
| + | [[http://www.uniprot.org/uniprot/THB_HUMAN THB_HUMAN]] Defects in THRB are the cause of generalized thyroid hormone resistance (GTHR) [MIM:[http://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:[http://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:[http://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 == | ||
| + | [[http://www.uniprot.org/uniprot/THB_HUMAN THB_HUMAN]] High affinity receptor for triiodothyronine.<ref>PMID:17418816</ref> [[http://www.uniprot.org/uniprot/RXRA_HUMAN RXRA_HUMAN]] Receptor for retinoic acid. Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expression in various biological processes. The RAR/RXR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. The high affinity ligand for RXRs is 9-cis retinoic acid. RXRA serves as a common heterodimeric partner for a number of nuclear receptors. The RXR/RAR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. In the absence of ligand, the RXR-RAR heterodimers associate with a multiprotein complex containing transcription corepressors that induce histone acetylation, chromatin condensation and transcriptional suppression. On ligand binding, the corepressors dissociate from the receptors and associate with the coactivators leading to transcriptional activation. The RXRA/PPARA heterodimer is required for PPARA transcriptional activity on fatty acid oxidation genes such as ACOX1 and the P450 system genes.<ref>PMID:10195690</ref> <ref>PMID:11162439</ref> <ref>PMID:11915042</ref> <ref>PMID:20215566</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | A subset of nuclear receptors (NRs) function as obligate heterodimers with retinoid X receptor (RXR), allowing integration of ligand-dependent signals across the dimer interface via an unknown structural mechanism. Using nuclear magnetic resonance (NMR) spectroscopy, x-ray crystallography and hydrogen/deuterium exchange (HDX) mass spectrometry, here we show an allosteric mechanism through which RXR co-operates with a permissive dimer partner, peroxisome proliferator-activated receptor (PPAR)-gamma, while rendered generally unresponsive by a non-permissive dimer partner, thyroid hormone (TR) receptor. Amino acid residues that mediate this allosteric mechanism comprise an evolutionarily conserved network discovered by statistical coupling analysis (SCA). This SCA network acts as a signalling rheostat to integrate signals between dimer partners, ligands and coregulator-binding sites, thereby affecting signal transmission in RXR heterodimers. These findings define rules guiding how NRs integrate two ligand-dependent signalling pathways into RXR heterodimer-specific responses. | ||
| - | + | Structural mechanism for signal transduction in RXR nuclear receptor heterodimers.,Kojetin DJ, Matta-Camacho E, Hughes TS, Srinivasan S, Nwachukwu JC, Cavett V, Nowak J, Chalmers MJ, Marciano DP, Kamenecka TM, Shulman AI, Rance M, Griffin PR, Bruning JB, Nettles KW Nat Commun. 2015 Aug 20;6:8013. doi: 10.1038/ncomms9013. PMID:26289479<ref>PMID:26289479</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | + | </div> | |
| - | + | == References == | |
| - | [[Category: | + | <references/> |
| - | [[Category: | + | __TOC__ |
| + | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
| + | [[Category: Bruning, J B]] | ||
| + | [[Category: Cavett, V]] | ||
| + | [[Category: Chalmers, M J]] | ||
| + | [[Category: Griffin, P R]] | ||
| + | [[Category: Hughes, T S]] | ||
| + | [[Category: Kamenecka, T M]] | ||
| + | [[Category: Kojetin, D J]] | ||
| + | [[Category: Mangelsdorf, D J]] | ||
| + | [[Category: Marciano, D P]] | ||
[[Category: Matta-Camacho, E]] | [[Category: Matta-Camacho, E]] | ||
| - | [[Category: | + | [[Category: Nettles, K W]] |
| - | + | ||
| - | + | ||
| - | + | ||
| - | + | ||
| - | + | ||
| - | + | ||
| - | + | ||
| - | + | ||
| - | + | ||
[[Category: Nowak, J]] | [[Category: Nowak, J]] | ||
| - | [[Category: | + | [[Category: Nwachukwu, J C]] |
[[Category: Rance, M]] | [[Category: Rance, M]] | ||
| - | [[Category: | + | [[Category: Shulman, A I]] |
| + | [[Category: Srinivasan, S]] | ||
| + | [[Category: Ligand binding]] | ||
| + | [[Category: Nuclear receptor]] | ||
| + | [[Category: Protein binding]] | ||
| + | [[Category: Protein-ligand complex]] | ||
| + | [[Category: Transcription factor]] | ||
Revision as of 12:21, 2 September 2015
Crystal Structure of the T3-bound TR-beta Ligand-binding Domain in complex with RXR-alpha
| |||||||||||
Categories: Homo sapiens | Bruning, J B | Cavett, V | Chalmers, M J | Griffin, P R | Hughes, T S | Kamenecka, T M | Kojetin, D J | Mangelsdorf, D J | Marciano, D P | Matta-Camacho, E | Nettles, K W | Nowak, J | Nwachukwu, J C | Rance, M | Shulman, A I | Srinivasan, S | Ligand binding | Nuclear receptor | Protein binding | Protein-ligand complex | Transcription factor
