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| | <StructureSection load='5g43' size='340' side='right'caption='[[5g43]], [[Resolution|resolution]] 2.58Å' scene=''> | | <StructureSection load='5g43' size='340' side='right'caption='[[5g43]], [[Resolution|resolution]] 2.58Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5g43]] 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=5G43 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5G43 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5g43]] 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=5G43 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5G43 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5IM:2-(1-PIPERIDINYL)-1,3-THIAZOL-4-AMINE'>5IM</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]] 2.58Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5g42|5g42]], [[5g44|5g44]], [[5g45|5g45]], [[5g46|5g46]]</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5IM:2-(1-PIPERIDINYL)-1,3-THIAZOL-4-AMINE'>5IM</scene></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5g43 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5g43 OCA], [http://pdbe.org/5g43 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5g43 RCSB], [http://www.ebi.ac.uk/pdbsum/5g43 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5g43 ProSAT]</span></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=5g43 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5g43 OCA], [https://pdbe.org/5g43 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5g43 RCSB], [https://www.ebi.ac.uk/pdbsum/5g43 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5g43 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | + | == Disease == |
| | + | [https://www.uniprot.org/uniprot/NCOA2_HUMAN NCOA2_HUMAN] Note=Chromosomal aberrations involving NCOA2 may be a cause of acute myeloid leukemias. Inversion inv(8)(p11;q13) generates the KAT6A-NCOA2 oncogene, which consists of the N-terminal part of KAT6A and the C-terminal part of NCOA2/TIF2. KAT6A-NCOA2 binds to CREBBP and disrupts its function in transcription activation. |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/RORG_HUMAN RORG_HUMAN]] Possible nuclear receptor for hydroxycholesterols, the binding of which strongly promotes coactivators recruitment. Essential for thymopoiesis and the development of several secondary lymphoid tissues, including lymph nodes. Involved in lineage specification of uncommitted CD4(+) T-helper cells into Th17 cells. Regulate the expression of several components of the circadian clock. | + | [https://www.uniprot.org/uniprot/NCOA2_HUMAN NCOA2_HUMAN] Transcriptional coactivator for steroid receptors and nuclear receptors. Coactivator of the steroid binding domain (AF-2) but not of the modulating N-terminal domain (AF-1). Required with NCOA1 to control energy balance between white and brown adipose tissues.<ref>PMID:9430642</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Guo, H]] | + | [[Category: Guo H]] |
| - | [[Category: Hillertz, P]] | + | [[Category: Hillertz P]] |
| - | [[Category: Xue, Y]] | + | [[Category: Xue Y]] |
| - | [[Category: Dna binding protein]]
| + | |
| - | [[Category: Fragment screen]]
| + | |
| - | [[Category: Rorg ligand]]
| + | |
| - | [[Category: Simultaneous binding]]
| + | |
| - | [[Category: Structure-based design]]
| + | |
| Structural highlights
Disease
NCOA2_HUMAN Note=Chromosomal aberrations involving NCOA2 may be a cause of acute myeloid leukemias. Inversion inv(8)(p11;q13) generates the KAT6A-NCOA2 oncogene, which consists of the N-terminal part of KAT6A and the C-terminal part of NCOA2/TIF2. KAT6A-NCOA2 binds to CREBBP and disrupts its function in transcription activation.
Function
NCOA2_HUMAN Transcriptional coactivator for steroid receptors and nuclear receptors. Coactivator of the steroid binding domain (AF-2) but not of the modulating N-terminal domain (AF-1). Required with NCOA1 to control energy balance between white and brown adipose tissues.[1]
Publication Abstract from PubMed
The retinoic-acid-related orphan receptor gamma t (RORgammat), as a master regulator of Th17 cell pathology, has become an attractive target for small-molecule drug discovery for the treatment of Th17-cell-related autoimmune diseases. A crystallographic fragment screening was carried out for RORgammat using the ligand binding domain. An overall hit rate of 5.5 % was obtained by screening 384 compounds in 96 cocktails. Five distinct hotspots were identified, and four regions of anchoring polar interactions were observed. In addition, significant induced fit was found for the binding of several fragments. Strikingly, a simultaneous binding of three fragments was revealed which presents interesting features including pi-pi stacking, multiple hydrogen bonds to the protein, and significant induced fit. Overall, the results offer a complete mapping of the ligand binding pocket and provide valuable inspiration in structure-based design for RORgammat lead generation and optimization. The crystallographic screening also resulted in fragment hits that bind at the surface away from the ligand binding pocket. This surface site is near the plausible dimer interface by analogy with other nuclear receptor systems, which can provide initial hints to explore alternative ways to modulate RORgammat through protein-protein interactions.
Fragment Screening of RORgammat Using Cocktail Crystallography: Identification of Simultaneous Binding of Multiple Fragments.,Xue Y, Guo H, Hillertz P ChemMedChem. 2016 Jul 19. doi: 10.1002/cmdc.201600242. PMID:27432277[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Voegel JJ, Heine MJ, Tini M, Vivat V, Chambon P, Gronemeyer H. The coactivator TIF2 contains three nuclear receptor-binding motifs and mediates transactivation through CBP binding-dependent and -independent pathways. EMBO J. 1998 Jan 15;17(2):507-19. PMID:9430642 doi:10.1093/emboj/17.2.507
- ↑ Xue Y, Guo H, Hillertz P. Fragment Screening of RORgammat Using Cocktail Crystallography: Identification of Simultaneous Binding of Multiple Fragments. ChemMedChem. 2016 Jul 19. doi: 10.1002/cmdc.201600242. PMID:27432277 doi:http://dx.doi.org/10.1002/cmdc.201600242
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