|
|
| Line 3: |
Line 3: |
| | <StructureSection load='5ufs' size='340' side='right'caption='[[5ufs]], [[Resolution|resolution]] 2.12Å' scene=''> | | <StructureSection load='5ufs' size='340' side='right'caption='[[5ufs]], [[Resolution|resolution]] 2.12Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5ufs]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Miscellaneous_nucleic_acid Miscellaneous nucleic acid]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5UFS OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5UFS FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5ufs]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Unidentified Unidentified]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5UFS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5UFS FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1TA:TRIAMCINOLONE+ACETONIDE'>1TA</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.118Å</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=5ufs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ufs OCA], [http://pdbe.org/5ufs PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ufs RCSB], [http://www.ebi.ac.uk/pdbsum/5ufs PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ufs ProSAT]</span></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1TA:TRIAMCINOLONE+ACETONIDE'>1TA</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=5ufs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ufs OCA], [https://pdbe.org/5ufs PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ufs RCSB], [https://www.ebi.ac.uk/pdbsum/5ufs PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ufs ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/A0A1X8XLE9_9ZZZZ A0A1X8XLE9_9ZZZZ] |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
| Line 23: |
Line 26: |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Miscellaneous nucleic acid]] | + | [[Category: Unidentified]] |
| - | [[Category: Ortlund, E A]] | + | [[Category: Ortlund EA]] |
| - | [[Category: Weikum, E R]] | + | [[Category: Weikum ER]] |
| - | [[Category: Glucocorticoid receptor]]
| + | |
| - | [[Category: Hormone receptor]]
| + | |
| - | [[Category: Ligand binding domain]]
| + | |
| - | [[Category: Nuclear receptor]]
| + | |
| Structural highlights
Function
A0A1X8XLE9_9ZZZZ
Publication Abstract from PubMed
The synthetic glucocorticoids (GCs) dexamethasone, mometasone furoate, and triamcinolone acetonide have been pharmaceutical mainstays to treat chronic inflammatory diseases. These drugs bind to the glucocorticoid receptor (GR), a ligand- activated transcription factor and member of the nuclear receptor superfamily. GR is widely recognized as a therapeutic target for its ability to counter pro-inflammatory signaling. Despite the popularity of GCs in the clinic, long-term use leads to numerous side effects, driving the need for new and improved drugs with less off-target pharmacology. X-ray crystal structures have played an important role in the drug-design process, permitting the characterization of robust structure-function relationships. However, steroid receptor ligand-binding domains (LBDs) are inherently unstable and their crystallization has required extensive mutagenesis to enhance expression and crystallization. Here, we utilize an ancestral variant of GR as a tool to generate a high- resolution crystal structure of GR in complex with the potent glucocorticoid triamcinolone acetonide (TA) and a fragment of the small heterodimer partner (SHP). Using structural analysis, molecular dynamics and biochemistry, we show that TA increases intramolecular contacts within the LBD to drive affinity and enhance stability of the receptor-ligand complex. These data support the emerging theme that ligand- induced receptor conformational dynamics at the mouth of the pocket play a major role in steroid receptor activation. This work also represents the first GR structure in complex with SHP, which has been suggested to play a role in modulating hepatic GR function.
Structural analysis of the glucocorticoid receptor ligand-binding domain in complex with triamcinolone acetonide and a fragment of the atypical coregulator, SHP.,Weikum ER, Okafor DC, D'Agostino EH, Colucci JK, Ortlund EA Mol Pharmacol. 2017 Apr 10. pii: mol.117.108506. doi: 10.1124/mol.117.108506. PMID:28396564[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Weikum ER, Okafor DC, D'Agostino EH, Colucci JK, Ortlund EA. Structural analysis of the glucocorticoid receptor ligand-binding domain in complex with triamcinolone acetonide and a fragment of the atypical coregulator, SHP. Mol Pharmacol. 2017 Apr 10. pii: mol.117.108506. doi: 10.1124/mol.117.108506. PMID:28396564 doi:http://dx.doi.org/10.1124/mol.117.108506
|
