7k6r
From Proteopedia
(Difference between revisions)
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==Crystal structure of the bromodomain (BD) of human Bromodomain and PHD finger-containing Transcription Factor (BPTF) bound to GSK4027== | ==Crystal structure of the bromodomain (BD) of human Bromodomain and PHD finger-containing Transcription Factor (BPTF) bound to GSK4027== | ||
| - | <StructureSection load='7k6r' size='340' side='right'caption='[[7k6r]]' scene=''> | + | <StructureSection load='7k6r' size='340' side='right'caption='[[7k6r]], [[Resolution|resolution]] 1.60Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7K6R OCA]. For a <b>guided tour on the structure components</b> use [ | + | <table><tr><td colspan='2'>[[7k6r]] is a 1 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=7K6R OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7K6R FirstGlance]. <br> |
| - | </td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.6Å</td></tr> |
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=9ST:4-bromo-2-methyl-5-[[(3~{R},5~{R})-1-methyl-5-phenyl-piperidin-3-yl]amino]pyridazin-3-one'>9ST</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</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=7k6r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7k6r OCA], [https://pdbe.org/7k6r PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7k6r RCSB], [https://www.ebi.ac.uk/pdbsum/7k6r PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7k6r ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/BPTF_HUMAN BPTF_HUMAN] Histone-binding component of NURF (nucleosome-remodeling factor), a complex which catalyzes ATP-dependent nucleosome sliding and facilitates transcription of chromatin. Specifically recognizes H3 tails trimethylated on 'Lys-4' (H3K4me3), which mark transcription start sites of virtually all active genes. May also regulate transcription through direct binding to DNA or transcription factors. | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Bromodomain-containing proteins regulate transcription through protein-protein interactions with chromatin and serve as scaffolding proteins for recruiting essential members of the transcriptional machinery. One such protein is the bromodomain and PHD-containing transcription factor (BPTF), the largest member of the nucleosome remodeling complex, NURF. Despite an emerging role for BPTF in regulating a diverse set of cancers, small molecule development for inhibiting the BPTF bromodomain has been lacking. Here we cross-validate three complementary biophysical assays to further the discovery of BPTF bromodomain inhibitors for chemical probe development: two direct binding assays (protein-observed 19F (PrOF) NMR and surface plasmon resonance (SPR)) and a competitive inhibition assay (AlphaScreen). We first compare the assays using three small molecules and acetylated histone peptides with reported affinity for the BPTF bromodomain. Using SPR with both unlabeled and fluorinated BPTF, we further determine that there is a minimal effect of 19F incorporation on ligand binding for future PrOF NMR experiments. To guide medicinal chemistry efforts towards chemical probe development, we subsequently evaluate two new BPTF inhibitor scaffolds with our suite of biophysical assays and rank-order compound affinities which could not otherwise be determined by PrOF NMR. Finally, we cocrystallize a subset of small molecule inhibitors and present the first published small molecule-protein structures with the BPTF bromodomain. We envision the biophysical assays described here and the structural insights from the crystallography will guide researchers towards developing selective and potent BPTF bromodomain inhibitors. | ||
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| + | New inhibitors for the BPTF bromodomain enabled by structural biology and biophysical assay development.,Ycas PD, Zahid H, Chan A, Olson NM, Johnson JA, Talluri SK, Schonbrunn E, Pomerantz WCK Org Biomol Chem. 2020 Jul 15;18(27):5174-5182. doi: 10.1039/d0ob00506a. PMID:32588860<ref>PMID:32588860</ref> | ||
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| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 7k6r" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Chan A]] | [[Category: Chan A]] | ||
[[Category: Schonbrunn E]] | [[Category: Schonbrunn E]] | ||
Current revision
Crystal structure of the bromodomain (BD) of human Bromodomain and PHD finger-containing Transcription Factor (BPTF) bound to GSK4027
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