7bde

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<StructureSection load='7bde' size='340' side='right'caption='[[7bde]], [[Resolution|resolution]] 2.04&Aring;' scene=''>
<StructureSection load='7bde' size='340' side='right'caption='[[7bde]], [[Resolution|resolution]] 2.04&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[7bde]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7BDE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7BDE FirstGlance]. <br>
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<table><tr><td colspan='2'>[[7bde]] 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=7BDE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7BDE FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=TEQ:5-[(5S,7R)-3-fluoranyl-7-(2-methylpyridin-3-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-5-yl]quinolin-2-amine'>TEQ</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.044&#8491;</td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BCL6, BCL5, LAZ3, ZBTB27, ZNF51 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=TEQ:5-[(5S,7R)-3-fluoranyl-7-(2-methylpyridin-3-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-5-yl]quinolin-2-amine'>TEQ</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=7bde FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7bde OCA], [https://pdbe.org/7bde PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7bde RCSB], [https://www.ebi.ac.uk/pdbsum/7bde PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7bde 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=7bde FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7bde OCA], [https://pdbe.org/7bde PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7bde RCSB], [https://www.ebi.ac.uk/pdbsum/7bde PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7bde ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
== Disease ==
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[[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.
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[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 ==
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[[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>
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[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>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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BCL6 is a zinc finger transcriptional repressor possessing a BTB-POZ domain, which is required for homodimerization and association with co-repressors. BCL6 has multiple roles in normal immunity, autoimmunity and some types of lymphoma. Mice bearing disrupted BCL6 loci demonstrate suppressed high affinity antibody responses to T-dependent antigens. The co-repressor binding groove in the BTB-POZ domain is a potential target for small compound mediated therapy. Several inhibitors targeting this binding groove have been described but these compounds have limited or absent in vivo activity. Biophysical studies of a novel compound, GSK137, showed an in vitro pIC50 = 8 and a cellular pIC50 = 7.3 for blocking binding of a peptide derived from the co-repressor silencing mediator for retinoid or thyroid-hormone receptors (SMRT) to the BCL6 BTB-POZ domain. The compound has good solubility (128 mug/mL) and permeability (86 nM/s). GSK137 caused little change in cell viability or proliferation in four BCL6 expressing B-cell lymphoma lines, although there was modest dose dependent accumulation of G1 phase cells. Pharmacokinetic studies in mice showed a profile compatible with achieving good levels of target engagement. GSK137, administered orally, suppressed IgG responses and reduced numbers of germinal centers and germinal center B-cells following immunisation of mice with the hapten trinitro-phenol (TNP). Overall, we report a novel small molecule BCL6 inhibitor with in vivo activity that inhibits the T-dependent antigen immune response.
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GSK137, a potent small molecule BCL6 inhibitor with in vivo activity, suppresses antibody responses in mice.,Pearce AC, Bamford MJ, Barber R, Bridges A, Convery MA, Demetriou C, Evans S, Gobbetti T, Hirst DJ, Holmes DS, Hutchinson JP, Jayne S, Lezina L, McCabe MT, Messenger C, Morley J, Musso MC, Scott-Stevens P, Manso AS, Schofield J, Slocombe T, Somers D, Walker AL, Wyce A, Zhang XP, Wagner SD J Biol Chem. 2021 Jul 15:100928. doi: 10.1016/j.jbc.2021.100928. PMID:34274316<ref>PMID:34274316</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 7bde" style="background-color:#fffaf0;"></div>
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== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Human]]
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[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Somers, D O]]
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[[Category: Somers DO]]
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[[Category: B-cell lymphoma]]
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[[Category: Btb domain]]
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[[Category: Inhibitor]]
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[[Category: Transcription]]
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[[Category: Transcriptional repression transcription]]
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Current revision

HUMAN BCL6 BTB-DOMAIN IN COMPLEX WITH GSK137

PDB ID 7bde

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Proteopedia Page Contributors and Editors (what is this?)

OCA

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