5cbx

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==AncGR DNA Binding Domain - (+)GRE Complex==
==AncGR DNA Binding Domain - (+)GRE Complex==
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<StructureSection load='5cbx' size='340' side='right' caption='[[5cbx]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
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<StructureSection load='5cbx' size='340' side='right'caption='[[5cbx]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[5cbx]] is a 8 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5CBX OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5CBX FirstGlance]. <br>
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<table><tr><td colspan='2'>[[5cbx]] is a 8 chain structure with sequence from [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct] and [https://en.wikipedia.org/wiki/Unidentified Unidentified]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5CBX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5CBX FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
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</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&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5cby|5cby]], [[5cbz|5cbz]], [[5cc0|5cc0]], [[5cc1|5cc1]]</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
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<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=5cbx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5cbx OCA], [http://pdbe.org/5cbx PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5cbx RCSB], [http://www.ebi.ac.uk/pdbsum/5cbx PDBsum]</span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5cbx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5cbx OCA], [https://pdbe.org/5cbx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5cbx RCSB], [https://www.ebi.ac.uk/pdbsum/5cbx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5cbx ProSAT]</span></td></tr>
</table>
</table>
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<div style="background-color:#fffaf0;">
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== Disease ==
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== Publication Abstract from PubMed ==
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[https://www.uniprot.org/uniprot/GCR_HUMAN GCR_HUMAN] Defects in NR3C1 are a cause of glucocorticoid resistance (GCRES) [MIM:[https://omim.org/entry/138040 138040]; also known as cortisol resistance. It is a hypertensive, hyperandrogenic disorder characterized by increased serum cortisol concentrations. Inheritance is autosomal dominant.<ref>PMID:12050230</ref> <ref>PMID:1704018</ref> <ref>PMID:7683692</ref> <ref>PMID:11589680</ref> <ref>PMID:11701741</ref>
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Many genomes contain families of paralogs--proteins with divergent function that evolved from a common ancestral gene after a duplication event. To understand how paralogous transcription factors evolve divergent DNA specificities, we examined how the glucocorticoid receptor and its paralogs evolved to bind activating response elements [(+)GREs] and negative glucocorticoid response elements (nGREs). We show that binding to nGREs is a property of the glucocorticoid receptor (GR) DNA-binding domain (DBD) not shared by other members of the steroid receptor family. Using phylogenetic, structural, biochemical, and molecular dynamics techniques, we show that the ancestral DBD from which GR and its paralogs evolved was capable of binding both nGRE and (+)GRE sequences because of the ancestral DBD's ability to assume multiple DNA-bound conformations. Subsequent amino acid substitutions in duplicated daughter genes selectively restricted protein conformational space, causing this dual DNA-binding specificity to be selectively enhanced in the GR lineage and lost in all others. Key substitutions that determined the receptors' response element-binding specificity were far from the proteins' DNA-binding interface and interacted epistatically to change the DBD's function through DNA-induced allosteric mechanisms. These amino acid substitutions subdivided both the conformational and functional space of the ancestral DBD among the present-day receptors, allowing a paralogous family of transcription factors to control disparate transcriptional programs despite high sequence identity.
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== Function ==
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[https://www.uniprot.org/uniprot/GCR_HUMAN GCR_HUMAN] Receptor for glucocorticoids (GC). Has a dual mode of action: as a transcription factor that binds to glucocorticoid response elements (GRE), both for nuclear and mitochondrial DNA, and as a modulator of other transcription factors. Affects inflammatory responses, cellular proliferation and differentiation in target tissues. Could act as a coactivator for STAT5-dependent transcription upon growth hormone (GH) stimulation and could reveal an essential role of hepatic GR in the control of body growth. Involved in chromatin remodeling. Plays a significant role in transactivation.<ref>PMID:21664385</ref>
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Distal substitutions drive divergent DNA specificity among paralogous transcription factors through subdivision of conformational space.,Hudson WH, Kossmann BR, de Vera IM, Chuo SW, Weikum ER, Eick GN, Thornton JW, Ivanov IN, Kojetin DJ, Ortlund EA Proc Natl Acad Sci U S A. 2016 Jan 12;113(2):326-31. doi:, 10.1073/pnas.1518960113. Epub 2015 Dec 29. PMID:26715749<ref>PMID:26715749</ref>
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==See Also==
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*[[Glucocorticoid receptor 3D structures|Glucocorticoid receptor 3D structures]]
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 5cbx" style="background-color:#fffaf0;"></div>
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== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Hudson, W H]]
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[[Category: Large Structures]]
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[[Category: Ortlund, E A]]
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[[Category: Synthetic construct]]
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[[Category: Dna binding protein]]
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[[Category: Unidentified]]
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[[Category: Dna binding protein-dna complex]]
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[[Category: Hudson WH]]
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[[Category: Ortlund EA]]

Current revision

AncGR DNA Binding Domain - (+)GRE Complex

PDB ID 5cbx

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