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| - | [[Image:3bqd.jpg|left|200px]]<br /><applet load="3bqd" size="350" color="white" frame="true" align="right" spinBox="true" | |
| - | caption="3bqd, resolution 2.50Å" /> | |
| - | '''Doubling the Size of the Glucocorticoid Receptor Ligand Binding Pocket by Deacylcortivazol'''<br /> | |
| | | | |
| - | ==Overview== | + | ==Doubling the Size of the Glucocorticoid Receptor Ligand Binding Pocket by Deacylcortivazol== |
| - | A common feature of nuclear receptor ligand binding domains (LBD) is a, helical sandwich fold that nests a ligand binding pocket within the bottom, half of the domain. Here we report that the ligand pocket of, glucocorticoid receptor (GR) can be continuously extended into the top, half of the LBD by binding to deacylcortivazol (DAC), an extremely potent, glucocorticoid. It has been puzzling for decades why DAC, which contains a, phenylpyrazole replacement at the conserved 3-ketone of steroid hormones, that are normally required for activation of their cognate receptors, is a, potent GR activator. The crystal structure of the GR LBD bound to DAC and, the fourth LXXLL motif of steroid receptor coactivator-1 reveals that the, GR ligand binding pocket is expanded to a size of 1070 A(3), effectively, doubling the size of the GR DEX-binding pocket of 540 A(3), and yet, leaving the structure of the coactivator binding site intact. DAC only, occupies approximately 50% of the space of the pocket but makes intricate, interactions with the receptor around the phenylpyrazole group that, accounts for the high affinity binding of DAC. The dramatic expansion of, the DAC-binding pocket thus highlights the conformational adaptability of, GR to ligand binding. The new structure also allows docking of various, nonsteroidal ligands that can not be fitted into the previous structures, thus providing a new rational template for drug discovery of steroidal and, non-steroidal glucocorticoids that can be specifically designed to reach, the unoccupied space of the expanded pocket. | + | <StructureSection load='3bqd' size='340' side='right'caption='[[3bqd]], [[Resolution|resolution]] 2.50Å' scene=''> |
| | + | == Structural highlights == |
| | + | <table><tr><td colspan='2'>[[3bqd]] is a 2 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=3BQD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3BQD 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]] 2.5Å</td></tr> |
| | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DAY:1-[(1R,2R,3AS,3BS,10AR,10BS,11S,12AS)-1,11-DIHYDROXY-2,5,10A,12A-TETRAMETHYL-7-PHENYL-1,2,3,3A,3B,7,10,10A,10B,11,12,12A-DODECAHYDROCYCLOPENTA[5,6]NAPHTHO[1,2-F]INDAZOL-1-YL]-2-HYDROXYETHANONE'>DAY</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=3bqd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3bqd OCA], [https://pdbe.org/3bqd PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3bqd RCSB], [https://www.ebi.ac.uk/pdbsum/3bqd PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3bqd ProSAT]</span></td></tr> |
| | + | </table> |
| | + | == Disease == |
| | + | [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> |
| | + | == Function == |
| | + | [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> |
| | + | == 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/bq/3bqd_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=3bqd ConSurf]. |
| | + | <div style="clear:both"></div> |
| | + | <div style="background-color:#fffaf0;"> |
| | + | == Publication Abstract from PubMed == |
| | + | A common feature of nuclear receptor ligand binding domains (LBD) is a helical sandwich fold that nests a ligand binding pocket within the bottom half of the domain. Here we report that the ligand pocket of glucocorticoid receptor (GR) can be continuously extended into the top half of the LBD by binding to deacylcortivazol (DAC), an extremely potent glucocorticoid. It has been puzzling for decades why DAC, which contains a phenylpyrazole replacement at the conserved 3-ketone of steroid hormones that are normally required for activation of their cognate receptors, is a potent GR activator. The crystal structure of the GR LBD bound to DAC and the fourth LXXLL motif of steroid receptor coactivator 1 reveals that the GR ligand binding pocket is expanded to a size of 1,070 A(3), effectively doubling the size of the GR dexamethasone-binding pocket of 540 A(3) and yet leaving the structure of the coactivator binding site intact. DAC occupies only approximately 50% of the space of the pocket but makes intricate interactions with the receptor around the phenylpyrazole group that accounts for the high-affinity binding of DAC. The dramatic expansion of the DAC-binding pocket thus highlights the conformational adaptability of GR to ligand binding. The new structure also allows docking of various nonsteroidal ligands that cannot be fitted into the previous structures, thus providing a new rational template for drug discovery of steroidal and nonsteroidal glucocorticoids that can be specifically designed to reach the unoccupied space of the expanded pocket. |
| | | | |
| - | ==About this Structure==
| + | Doubling the size of the glucocorticoid receptor ligand binding pocket by deacylcortivazol.,Suino-Powell K, Xu Y, Zhang C, Tao YG, Tolbert WD, Simons SS Jr, Xu HE Mol Cell Biol. 2008 Mar;28(6):1915-23. Epub 2007 Dec 26. PMID:18160712<ref>PMID:18160712</ref> |
| - | 3BQD is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=DAY:'>DAY</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Histone_acetyltransferase Histone acetyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.3.1.48 2.3.1.48] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3BQD OCA].
| + | |
| | | | |
| - | ==Reference==
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| - | Doubling the Size of the Glucocorticoid Receptor Ligand Binding Pocket by Deacylcortivazol., Suino-Powell K, Xu Y, Zhang C, Tao YG, Tolbert WD, Simons SS Jr, Xu HE, Mol Cell Biol. 2007 Dec 26;. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=18160712 18160712]
| + | </div> |
| - | [[Category: Histone acetyltransferase]]
| + | <div class="pdbe-citations 3bqd" style="background-color:#fffaf0;"></div> |
| - | [[Category: Homo sapiens]]
| + | |
| - | [[Category: Protein complex]]
| + | |
| - | [[Category: Xu, H.E.]]
| + | |
| - | [[Category: DAY]]
| + | |
| - | [[Category: acyltransferase]]
| + | |
| - | [[Category: alternative initiation]]
| + | |
| - | [[Category: alternative splicing]]
| + | |
| - | [[Category: charge clamp]]
| + | |
| - | [[Category: chromatin regulator]]
| + | |
| - | [[Category: chromosomal rearrangement]]
| + | |
| - | [[Category: coactivator ]]
| + | |
| - | [[Category: cytoplasm]]
| + | |
| - | [[Category: deacylcortivazol]]
| + | |
| - | [[Category: dimer interface]]
| + | |
| - | [[Category: disease mutation]]
| + | |
| - | [[Category: dna-binding]]
| + | |
| - | [[Category: glucocorticoid receptor]]
| + | |
| - | [[Category: hormone binding pocket]]
| + | |
| - | [[Category: lipid-binding]]
| + | |
| - | [[Category: metal-binding]]
| + | |
| - | [[Category: nuclear receptor coactivator 1 isoform 1]]
| + | |
| - | [[Category: nucleus]]
| + | |
| - | [[Category: phosphoprotein]]
| + | |
| - | [[Category: polymorphism]]
| + | |
| - | [[Category: protein binding]]
| + | |
| - | [[Category: proto-oncogene]]
| + | |
| - | [[Category: pseudohermaphroditism]]
| + | |
| - | [[Category: src1]]
| + | |
| - | [[Category: steroid-binding]]
| + | |
| - | [[Category: transcription]]
| + | |
| - | [[Category: transcription regulation]]
| + | |
| - | [[Category: transferase]]
| + | |
| - | [[Category: ubl conjugation]]
| + | |
| - | [[Category: zinc]]
| + | |
| - | [[Category: zinc-finger]]
| + | |
| | | | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 11:11:56 2008''
| + | ==See Also== |
| | + | *[[Glucocorticoid receptor 3D structures|Glucocorticoid receptor 3D structures]] |
| | + | == References == |
| | + | <references/> |
| | + | __TOC__ |
| | + | </StructureSection> |
| | + | [[Category: Homo sapiens]] |
| | + | [[Category: Large Structures]] |
| | + | [[Category: Xu HE]] |
| Structural highlights
Disease
GCR_HUMAN Defects in NR3C1 are a cause of glucocorticoid resistance (GCRES) [MIM:138040; also known as cortisol resistance. It is a hypertensive, hyperandrogenic disorder characterized by increased serum cortisol concentrations. Inheritance is autosomal dominant.[1] [2] [3] [4] [5]
Function
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.[6]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
A common feature of nuclear receptor ligand binding domains (LBD) is a helical sandwich fold that nests a ligand binding pocket within the bottom half of the domain. Here we report that the ligand pocket of glucocorticoid receptor (GR) can be continuously extended into the top half of the LBD by binding to deacylcortivazol (DAC), an extremely potent glucocorticoid. It has been puzzling for decades why DAC, which contains a phenylpyrazole replacement at the conserved 3-ketone of steroid hormones that are normally required for activation of their cognate receptors, is a potent GR activator. The crystal structure of the GR LBD bound to DAC and the fourth LXXLL motif of steroid receptor coactivator 1 reveals that the GR ligand binding pocket is expanded to a size of 1,070 A(3), effectively doubling the size of the GR dexamethasone-binding pocket of 540 A(3) and yet leaving the structure of the coactivator binding site intact. DAC occupies only approximately 50% of the space of the pocket but makes intricate interactions with the receptor around the phenylpyrazole group that accounts for the high-affinity binding of DAC. The dramatic expansion of the DAC-binding pocket thus highlights the conformational adaptability of GR to ligand binding. The new structure also allows docking of various nonsteroidal ligands that cannot be fitted into the previous structures, thus providing a new rational template for drug discovery of steroidal and nonsteroidal glucocorticoids that can be specifically designed to reach the unoccupied space of the expanded pocket.
Doubling the size of the glucocorticoid receptor ligand binding pocket by deacylcortivazol.,Suino-Powell K, Xu Y, Zhang C, Tao YG, Tolbert WD, Simons SS Jr, Xu HE Mol Cell Biol. 2008 Mar;28(6):1915-23. Epub 2007 Dec 26. PMID:18160712[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Vottero A, Kino T, Combe H, Lecomte P, Chrousos GP. A novel, C-terminal dominant negative mutation of the GR causes familial glucocorticoid resistance through abnormal interactions with p160 steroid receptor coactivators. J Clin Endocrinol Metab. 2002 Jun;87(6):2658-67. PMID:12050230
- ↑ Hurley DM, Accili D, Stratakis CA, Karl M, Vamvakopoulos N, Rorer E, Constantine K, Taylor SI, Chrousos GP. Point mutation causing a single amino acid substitution in the hormone binding domain of the glucocorticoid receptor in familial glucocorticoid resistance. J Clin Invest. 1991 Feb;87(2):680-6. PMID:1704018 doi:http://dx.doi.org/10.1172/JCI115046
- ↑ Malchoff DM, Brufsky A, Reardon G, McDermott P, Javier EC, Bergh CH, Rowe D, Malchoff CD. A mutation of the glucocorticoid receptor in primary cortisol resistance. J Clin Invest. 1993 May;91(5):1918-25. PMID:7683692 doi:http://dx.doi.org/10.1172/JCI116410
- ↑ Ruiz M, Lind U, Gafvels M, Eggertsen G, Carlstedt-Duke J, Nilsson L, Holtmann M, Stierna P, Wikstrom AC, Werner S. Characterization of two novel mutations in the glucocorticoid receptor gene in patients with primary cortisol resistance. Clin Endocrinol (Oxf). 2001 Sep;55(3):363-71. PMID:11589680
- ↑ Kino T, Stauber RH, Resau JH, Pavlakis GN, Chrousos GP. Pathologic human GR mutant has a transdominant negative effect on the wild-type GR by inhibiting its translocation into the nucleus: importance of the ligand-binding domain for intracellular GR trafficking. J Clin Endocrinol Metab. 2001 Nov;86(11):5600-8. PMID:11701741
- ↑ Psarra AM, Sekeris CE. Glucocorticoids induce mitochondrial gene transcription in HepG2 cells: role of the mitochondrial glucocorticoid receptor. Biochim Biophys Acta. 2011 Oct;1813(10):1814-21. doi:, 10.1016/j.bbamcr.2011.05.014. Epub 2011 Jun 2. PMID:21664385 doi:10.1016/j.bbamcr.2011.05.014
- ↑ Suino-Powell K, Xu Y, Zhang C, Tao YG, Tolbert WD, Simons SS Jr, Xu HE. Doubling the size of the glucocorticoid receptor ligand binding pocket by deacylcortivazol. Mol Cell Biol. 2008 Mar;28(6):1915-23. Epub 2007 Dec 26. PMID:18160712 doi:10.1128/MCB.01541-07
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