6c3l
From Proteopedia
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==Crystal structure of BCL6 BTB domain with compound 15f== | ==Crystal structure of BCL6 BTB domain with compound 15f== | ||
| - | <StructureSection load='6c3l' size='340' side='right' caption='[[6c3l]], [[Resolution|resolution]] 1.46Å' scene=''> | + | <StructureSection load='6c3l' size='340' side='right'caption='[[6c3l]], [[Resolution|resolution]] 1.46Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>[[6c3l]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6C3L OCA]. For a <b>guided tour on the structure components</b> use [ | + | <table><tr><td colspan='2'>[[6c3l]] 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=6C3L OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6C3L FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EGP:N-[2-(1H-indol-3-yl)ethyl]-N-{3-[(4-methylpiperazin-1-yl)methyl]-1-[2-(morpholin-4-yl)-2-oxoethyl]-1H-indol-6-yl}thiourea'>EGP</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]] 1.4609215Å</td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EGP:N-[2-(1H-indol-3-yl)ethyl]-N-{3-[(4-methylpiperazin-1-yl)methyl]-1-[2-(morpholin-4-yl)-2-oxoethyl]-1H-indol-6-yl}thiourea'>EGP</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=6c3l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6c3l OCA], [https://pdbe.org/6c3l PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6c3l RCSB], [https://www.ebi.ac.uk/pdbsum/6c3l PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6c3l ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Disease == | == 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 == | == 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 == | ||
| + | Protein-protein interactions (PPI) between the transcriptional repressor B-cell lymphoma 6 (BCL6) BTB domain (BCL6(BTB)) and its corepressors have emerged as a promising target for anticancer therapeutics. However, identification of potent, drug-like inhibitors of BCL6(BTB) has remained challenging. Using NMR-based screening of a library of fragment-like small molecules, we have identified a thiourea compound (7CC5) that binds to BCL6(BTB). From this hit, the application of computer-aided drug design (CADD), medicinal chemistry, NMR spectroscopy, and X-ray crystallography has yielded an inhibitor, 15f, that demonstrated over 100-fold improved potency for BCL6(BTB). This gain in potency was achieved by a unique binding mode that mimics the binding mode of the corepressor SMRT in the aromatic and the HDCH sites. The structure-activity relationship based on these new inhibitors will have a significant impact on the rational design of novel BCL6 inhibitors, facilitating the identification of therapeutics for the treatment of BCL6-dependent tumors. | ||
| + | |||
| + | Identification of Thiourea-Based Inhibitors of the B-Cell Lymphoma 6 BTB Domain via NMR-Based Fragment Screening and Computer-Aided Drug Design.,Cheng H, Linhares BM, Yu W, Cardenas MG, Ai Y, Jiang W, Winkler A, Cohen S, Melnick A, MacKerell A Jr, Cierpicki T, Xue F J Med Chem. 2018 Sep 13;61(17):7573-7588. doi: 10.1021/acs.jmedchem.8b00040. Epub, 2018 Jul 17. PMID:29969259<ref>PMID:29969259</ref> | ||
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| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 6c3l" style="background-color:#fffaf0;"></div> | ||
| + | |||
| + | ==See Also== | ||
| + | *[[B-cell lymphoma proteins 3D structures|B-cell lymphoma proteins 3D structures]] | ||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| - | [[Category: | + | [[Category: Homo sapiens]] |
| - | [[Category: | + | [[Category: Large Structures]] |
| - | [[Category: | + | [[Category: Cheng H]] |
| - | [[Category: | + | [[Category: Cierpicki T]] |
| - | [[Category: | + | [[Category: Linhares B]] |
| - | [[Category: | + | [[Category: Xue F]] |
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Current revision
Crystal structure of BCL6 BTB domain with compound 15f
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