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==Crystal structure of the BCL6 BTB domain in complex with anilinopyrimidine ligand== | |||
<StructureSection load='6ew6' size='340' side='right'caption='[[6ew6]], [[Resolution|resolution]] 1.39Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6ew6]] 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=6EW6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6EW6 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]] 1.39Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=C0H:~{N}2-(2-chlorophenyl)-1,3,5-triazine-2,4-diamine'>C0H</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=6ew6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ew6 OCA], [https://pdbe.org/6ew6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6ew6 RCSB], [https://www.ebi.ac.uk/pdbsum/6ew6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6ew6 ProSAT]</span></td></tr> | |||
</table> | |||
== Disease == | |||
[https://www.uniprot.org/uniprot/BCL6_HUMAN BCL6_HUMAN] Note=Chromosomal aberrations involving BCL6 may be a cause of B-cell non-Hodgkin lymphoma. Translocation t(3;14)(q27;q32); translocation t(3;22)(q27;q11) with immunoglobulin gene regions. Note=A chromosomal aberration involving BCL6 may be a cause of a form of B-cell leukemia. Translocation t(3;11)(q27;q23) with POU2AF1/OBF1. Note=A chromosomal aberration involving BCL6 may be a cause of lymphoma. Translocation t(3;4)(q27;p11) with ARHH/TTF. | |||
== Function == | |||
[https://www.uniprot.org/uniprot/BCL6_HUMAN BCL6_HUMAN] Transcriptional repressor which is required for germinal center formation and antibody affinity maturation. Probably plays an important role in lymphomagenesis.<ref>PMID:9649500</ref> <ref>PMID:18280243</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
B-cell lymphoma 6 (BCL6) inhibition is a promising mechanism for treating hematological cancers but high quality chemical probes are necessary to evaluate its therapeutic potential. Here we report potent BCL6 inhibitors that demonstrate cellular target engagement and exhibit exquisite selectivity for BCL6 based on mass spectrometry analyses following chemical proteomic pull down. Importantly, a proteolysis-targeting chimera (PROTAC) was also developed and shown to significantly degrade BCL6 in a number of diffuse large B-cell lymphoma (DLBCL) cell lines, but neither BCL6 inhibition nor degradation selectively induced marked phenotypic response. To investigate, we monitored PROTAC directed BCL6 degradation in DLBCL OCI-Ly1 cells by immunofluorescence and discovered a residual BCL6 population. Analysis of subcellular fractions also showed incomplete BCL6 degradation in all fractions despite having measurable PROTAC concentrations, together providing a rationale for the weak antiproliferative response seen with both BCL6 inhibitor and degrader. In summary, we have developed potent and selective BCL6 inhibitors and a BCL6 PROTAC that effectively degraded BCL6, but both modalities failed to induce a significant phenotypic response in DLBCL despite achieving cellular concentrations. | |||
Development of a Novel B-Cell Lymphoma 6 (BCL6) PROTAC To Provide Insight into Small Molecule Targeting of BCL6.,McCoull W, Cheung T, Anderson E, Barton P, Burgess J, Byth K, Cao Q, Castaldi MP, Chen H, Chiarparin E, Carbajo RJ, Code E, Cowan S, Davey PR, Ferguson AD, Fillery S, Fuller NO, Gao N, Hargreaves D, Howard MR, Hu J, Kawatkar A, Kemmitt PD, Leo E, Molina DM, O'Connell N, Petteruti P, Rasmusson T, Raubo P, Rawlins PB, Ricchiuto P, Robb GR, Schenone M, Waring MJ, Zinda M, Fawell S, Wilson DM ACS Chem Biol. 2018 Oct 17. doi: 10.1021/acschembio.8b00698. PMID:30335946<ref>PMID:30335946</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 6ew6" style="background-color:#fffaf0;"></div> | ||
[[Category: Hargreaves | |||
[[Category: | ==See Also== | ||
*[[B-cell lymphoma proteins 3D structures|B-cell lymphoma proteins 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Ferguson A]] | |||
[[Category: Hargreaves D]] | |||
[[Category: Robb G]] | |||