6toh

From Proteopedia

(Difference between revisions)

Current revision

Crystal structure of human BCL6 BTB domain in complex with compound 6

Structural highlights

6toh is a 2 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.58Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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 PubMed

Deregulation of the transcriptional repressor BCL6 enables tumorigenesis of germinal center B-cells, and hence BCL6 has been proposed as a therapeutic target for the treatment of diffuse large B-cell lymphoma (DLBCL). Herein we report the discovery of a series of benzimidazolone inhibitors of the protein-protein interaction between BCL6 and its co-repressors. A subset of these inhibitors were found to cause rapid degradation of BCL6, and optimization of pharmacokinetic properties led to the discovery of 5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)am ino)-3-(3-hydroxy-3-methylbutyl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (CCT369260), which reduces BCL6 levels in a lymphoma xenograft mouse model following oral dosing.

Achieving In Vivo Target Depletion through the Discovery and Optimization of Benzimidazolone BCL6 Degraders.,Bellenie BR, Cheung KJ, Varela A, Pierrat OA, Collie GW, Box GM, Bright MD, Gowan S, Hayes A, Rodrigues MJ, Shetty KN, Carter M, Davis OA, Henley AT, Innocenti P, Johnson LD, Liu M, de Klerk S, Le Bihan YV, Lloyd MG, McAndrew PC, Shehu E, Talbot R, Woodward HL, Burke R, Kirkin V, van Montfort RLM, Raynaud FI, Rossanese OW, Hoelder S J Med Chem. 2020 Apr 10. doi: 10.1021/acs.jmedchem.9b02076. PMID:32275432^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Niu H, Ye BH, Dalla-Favera R. Antigen receptor signaling induces MAP kinase-mediated phosphorylation and degradation of the BCL-6 transcription factor. Genes Dev. 1998 Jul 1;12(13):1953-61. PMID:9649500
↑ Ghetu AF, Corcoran CM, Cerchietti L, Bardwell VJ, Melnick A, Prive GG. Structure of a BCOR corepressor peptide in complex with the BCL6 BTB domain dimer. Mol Cell. 2008 Feb 15;29(3):384-91. PMID:18280243 doi:10.1016/j.molcel.2007.12.026
↑ Bellenie BR, Cheung KJ, Varela A, Pierrat OA, Collie GW, Box GM, Bright MD, Gowan S, Hayes A, Rodrigues MJ, Shetty KN, Carter M, Davis OA, Henley AT, Innocenti P, Johnson LD, Liu M, de Klerk S, Le Bihan YV, Lloyd MG, McAndrew PC, Shehu E, Talbot R, Woodward HL, Burke R, Kirkin V, van Montfort RLM, Raynaud FI, Rossanese OW, Hoelder S. Achieving In Vivo Target Depletion through the Discovery and Optimization of Benzimidazolone BCL6 Degraders. J Med Chem. 2020 Apr 10. doi: 10.1021/acs.jmedchem.9b02076. PMID:32275432 doi:http://dx.doi.org/10.1021/acs.jmedchem.9b02076

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6toh"

@@ Line 3: / Line 3: @@
 <StructureSection load='6toh' size='340' side='right'caption='[[6toh]], [[Resolution|resolution]] 1.58&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6toh]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6TOH OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6TOH FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6toh]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6TOH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6TOH FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NQK:2-chloranyl-4-[(1,3-dimethyl-2-oxidanylidene-benzimidazol-5-yl)amino]pyridine-3-carbonitrile'>NQK</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]] 1.58&#8491;</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BCL6, BCL5, LAZ3, ZBTB27, ZNF51 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NQK:2-chloranyl-4-[(1,3-dimethyl-2-oxidanylidene-benzimidazol-5-yl)amino]pyridine-3-carbonitrile'>NQK</scene></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6toh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6toh OCA], [http://pdbe.org/6toh PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6toh RCSB], [http://www.ebi.ac.uk/pdbsum/6toh PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6toh 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=6toh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6toh OCA], [https://pdbe.org/6toh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6toh RCSB], [https://www.ebi.ac.uk/pdbsum/6toh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6toh ProSAT]</span></td></tr>
 </table>
 == Disease ==
-[[http://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.
+[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 ==
-[[http://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>
+[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 ==
@@ Line 21: / Line 21: @@
 </div>
 <div class="pdbe-citations 6toh" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[B-cell lymphoma proteins 3D structures|B-cell lymphoma proteins 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Bihan, Y V.Le]]
+[[Category: Synthetic construct]]
-[[Category: Collie, G W]]
+[[Category: Collie GW]]
-[[Category: Montfort, R L.M van]]
+[[Category: Le Bihan Y-V]]
-[[Category: Rodrigues, M J]]
+[[Category: Rodrigues MJ]]
-[[Category: Shetty, K]]
+[[Category: Shetty K]]
-[[Category: Cancer]]
+[[Category: Van Montfort RLM]]
-[[Category: Degrader]]
-[[Category: Inhibitor]]
-[[Category: Lymphoma]]
-[[Category: Transcription]]

6toh

From Proteopedia

Current revision

Crystal structure of human BCL6 BTB domain in complex with compound 6

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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