5n1x: Difference between revisions
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==Crystal structure of the BCL6 BTB domain in complex with pyrazolo-pyrimidine ligand== | ==Crystal structure of the BCL6 BTB domain in complex with pyrazolo-pyrimidine ligand== | ||
<StructureSection load='5n1x' size='340' side='right' caption='[[5n1x]], [[Resolution|resolution]] 1.72Å' scene=''> | <StructureSection load='5n1x' size='340' side='right'caption='[[5n1x]], [[Resolution|resolution]] 1.72Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[5n1x]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5N1X OCA]. For a <b>guided tour on the structure components</b> use [http:// | <table><tr><td colspan='2'>[[5n1x]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5N1X OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5N1X FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=8HH:~{N}-ETHYL-5-PYRIDIN-3-YL-PYRAZOLO[1,5-A]PYRIMIDIN-7-AMINE'>8HH</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=8HH:~{N}-ETHYL-5-PYRIDIN-3-YL-PYRAZOLO[1,5-A]PYRIMIDIN-7-AMINE'>8HH</scene></td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http:// | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5n1x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5n1x OCA], [http://pdbe.org/5n1x PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5n1x RCSB], [http://www.ebi.ac.uk/pdbsum/5n1x PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5n1x ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Disease == | == Disease == | ||
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</div> | </div> | ||
<div class="pdbe-citations 5n1x" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 5n1x" 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: Large Structures]] | |||
[[Category: Ferguson, A]] | [[Category: Ferguson, A]] | ||
[[Category: Hargreaves, D]] | [[Category: Hargreaves, D]] | ||
Revision as of 14:56, 26 August 2020
Crystal structure of the BCL6 BTB domain in complex with pyrazolo-pyrimidine ligandCrystal structure of the BCL6 BTB domain in complex with pyrazolo-pyrimidine ligand
Structural highlights
Disease[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[BCL6_HUMAN] Transcriptional repressor which is required for germinal center formation and antibody affinity maturation. Probably plays an important role in lymphomagenesis.[1] [2] Publication Abstract from PubMedInhibition of the protein-protein interaction between B-cell lymphoma 6 (BCL6) and corepressors has been implicated as a therapeutic target in diffuse large B-cell lymphoma (DLBCL) cancers and profiling of potent and selective BCL6 inhibitors are critical to test this hypothesis. We identified a pyrazolo[1,5-a]pyrimidine series of BCL6 binders from a fragment screen in parallel with a virtual screen. Using structure-based drug design, binding affinity was increased 100000-fold. This involved displacing crystallographic water, forming new ligand-protein interactions and a macrocyclization to favor the bioactive conformation of the ligands. Optimization for slow off-rate constant kinetics was conducted as well as improving selectivity against an off-target kinase, CK2. Potency in a cellular BCL6 assay was further optimized to afford highly selective probe molecules. Only weak antiproliferative effects were observed across a number of DLBCL lines and a multiple myeloma cell line without a clear relationship to BCL6 potency. As a result, we conclude that the BCL6 hypothesis in DLBCL cancer remains unproven. Discovery of Pyrazolo[1,5-a]pyrimidine B-Cell Lymphoma 6 (BCL6) Binders and Optimization to High Affinity Macrocyclic Inhibitors.,McCoull W, Abrams RD, Anderson E, Blades K, Barton P, Box M, Burgess J, Byth K, Cao Q, Chuaqui C, Carbajo RJ, Cheung T, Code E, Ferguson AD, Fillery S, Fuller NO, Gangl E, Gao N, Grist M, Hargreaves D, Howard MR, Hu J, Kemmitt PD, Nelson JE, O'Connell N, Prince DB, Raubo P, Rawlins PB, Robb GR, Shi J, Waring MJ, Whittaker D, Wylot M, Zhu X J Med Chem. 2017 May 9. doi: 10.1021/acs.jmedchem.7b00359. PMID:28485934[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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