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6kke

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<StructureSection load='6kke' size='340' side='right'caption='[[6kke]], [[Resolution|resolution]] 2.58&Aring;' scene=''>
<StructureSection load='6kke' size='340' side='right'caption='[[6kke]], [[Resolution|resolution]] 2.58&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[6kke]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6KKE OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6KKE FirstGlance]. <br>
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<table><tr><td colspan='2'>[[6kke]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6KKE OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6KKE FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=8HO:2-[(1-methyl-4-oxidanyl-7-phenoxy-isoquinolin-3-yl)carbonylamino]ethanoic+acid'>8HO</scene></td></tr>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=8HO:2-[(1-methyl-4-oxidanyl-7-phenoxy-isoquinolin-3-yl)carbonylamino]ethanoic+acid'>8HO</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6acm|6acm]]</td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6acm|6acm]]</td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">THRB, ERBA2, NR1A2, THR1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=6kke FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6kke OCA], [http://pdbe.org/6kke PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6kke RCSB], [http://www.ebi.ac.uk/pdbsum/6kke PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6kke ProSAT]</span></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=6kke FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6kke OCA], [http://pdbe.org/6kke PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6kke RCSB], [http://www.ebi.ac.uk/pdbsum/6kke PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6kke ProSAT]</span></td></tr>
</table>
</table>
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<div style="background-color:#fffaf0;">
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
== Publication Abstract from PubMed ==
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Nuclear receptors are important transcriptional factors that share high sequence identity and conserved domains, including a DNA-binding domain (DBD) and a ligand-binding domain (LBD). The LBD plays a crucial role in ligand-mediated nuclear receptor activity. Hundreds of different crystal structures of nuclear receptors have revealed a general mechanism for the molecular basis of ligand binding and ligand-mediated regulation of nuclear receptors. Despite the conserved fold of nuclear receptor LBDs, the ligand-binding pocket is the least conserved region among different nuclear receptor LBDs. Structural comparison and analysis show that several features of the pocket, like the size and also the shape, have contributed to the ligand binding affinity and specificity. In addition, the plastic nature of the ligand-binding pockets in many nuclear receptors provides greater flexibility to further accommodate specific ligands with a variety of conformations. Nuclear receptor coactivators usually contain multiple LXXLL motifs that are used to interact with nuclear receptors. The nuclear receptors respond differently to distinct ligands and readily exchange their ligands in different environments. The conformational flexibility of the AF-2 helix allows the nuclear receptor to sense the presence of the bound ligands, either an agonist or an antagonist, and to recruit the coactivators or corepressors that ultimately determine the transcriptional activation or repression of nuclear receptors.
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Resistance to thyroid hormone (RTH) is a clinical disorder without specific and effective therapeutic strategy, partly due to the lack of structural mechanisms for the defective ligand binding by mutated thyroid hormone receptors (THRs). We herein uncovered the prescription drug roxadustat as a novel THRbeta-selective ligand with therapeutic potentials in treating RTH, thereby providing a small molecule tool enabling the first probe into the structural mechanisms of RTH. Despite a wide distribution of the receptor mutation sites, different THRbeta mutants induce allosteric conformational modulation on the same His435 residue, which disrupts a critical hydrogen bond required for the binding of thyroid hormones. Interestingly, roxadustat retains hydrophobic interactions with THRbeta via its unique phenyl extension, enabling the rescue of the activity of the THRbeta mutants. Our study thus reveals a critical receptor allosterism mechanism for RTH by mutant THRbeta, providing a new and viable therapeutic strategy for the treatment of RTH.
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Structural and functional insights into nuclear receptor signaling.,Jin L, Li Y Adv Drug Deliv Rev. 2010 Oct 30;62(13):1218-26. doi: 10.1016/j.addr.2010.08.007. , Epub 2010 Aug 17. PMID:20723571<ref>PMID:20723571</ref>
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Revealing a Mutant-Induced Receptor Allosteric Mechanism for the Thyroid Hormone Resistance.,Yao B, Wei Y, Zhang S, Tian S, Xu S, Wang R, Zheng W, Li Y iScience. 2019 Oct 25;20:489-496. doi: 10.1016/j.isci.2019.10.002. Epub 2019 Oct , 2. PMID:31655060<ref>PMID:31655060</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Human]]
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Li, Y]]
[[Category: Li, Y]]

Revision as of 07:09, 4 March 2020

THRb mutation with a novel agonist

PDB ID 6kke

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