5x4m: Difference between revisions

Revision as of 13:36, 24 May 2017

Crystal structure of the BCL6 BTB domain in complex with Compound 1

Structural highlights

5x4m is a 1 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	7ZF
Related:	5x4n, 5x4o, 5x4p, 5x4q
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

B-cell lymphoma 6 (BCL6) is a transcriptional factor that expresses in lymphocytes and regulates the differentiation and proliferation of lymphocytes. Therefore, BCL6 is a therapeutic target for autoimmune diseases and cancer treatment. This report presents the discovery of BCL6-corepressor interaction inhibitors by using a biophysics-driven fragment-based approach. Using the surface plasmon resonance (SPR)-based fragment screening, we successfully identified fragment 1 (SPR KD = 1200 muM, ligand efficiency (LE) = 0.28), a competitive binder to the natural ligand BCoR peptide. Moreover, we elaborated 1 into the more potent compound 7 (SPR KD = 0.078 muM, LE = 0.37, cell-free protein-protein interaction (PPI) IC50 = 0.48 muM (ELISA), cellular PPI IC50 = 8.6 muM (M2H)) by a structure-based design and structural integration with a second high-throughput screening hit.

Discovery of a B-Cell Lymphoma 6 Protein-Protein Interaction Inhibitor by a Biophysics-Driven Fragment-Based Approach.,Kamada Y, Sakai N, Sogabe S, Ida K, Oki H, Sakamoto K, Lane W, Snell G, Iida M, Imaeda Y, Sakamoto J, Matsui J J Med Chem. 2017 May 11. doi: 10.1021/acs.jmedchem.7b00313. PMID:28471657^[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
↑ Kamada Y, Sakai N, Sogabe S, Ida K, Oki H, Sakamoto K, Lane W, Snell G, Iida M, Imaeda Y, Sakamoto J, Matsui J. Discovery of a B-Cell Lymphoma 6 Protein-Protein Interaction Inhibitor by a Biophysics-Driven Fragment-Based Approach. J Med Chem. 2017 May 11. doi: 10.1021/acs.jmedchem.7b00313. PMID:28471657 doi:https://dx.doi.org/10.1021/acs.jmedchem.7b00313

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] 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

[2] 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

[3] Kamada Y, Sakai N, Sogabe S, Ida K, Oki H, Sakamoto K, Lane W, Snell G, Iida M, Imaeda Y, Sakamoto J, Matsui J. Discovery of a B-Cell Lymphoma 6 Protein-Protein Interaction Inhibitor by a Biophysics-Driven Fragment-Based Approach. J Med Chem. 2017 May 11. doi: 10.1021/acs.jmedchem.7b00313. PMID:28471657 doi:https://dx.doi.org/10.1021/acs.jmedchem.7b00313

[1]

[2]

[3]

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 5x4m is ON HOLD  until Paper Publication
+==Crystal structure of the BCL6 BTB domain in complex with Compound 1==
+<StructureSection load='5x4m' size='340' side='right' caption='[[5x4m]], [[Resolution|resolution]] 1.65&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[5x4m]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5X4M OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5X4M FirstGlance]. <br>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=7ZF:N-PHENYL-1,3,5-TRIAZINE-2,4-DIAMINE'>7ZF</scene></td></tr>
+<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5x4n|5x4n]], [[5x4o|5x4o]], [[5x4p|5x4p]], [[5x4q|5x4q]]</td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5x4m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5x4m OCA], [http://pdbe.org/5x4m PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5x4m RCSB], [http://www.ebi.ac.uk/pdbsum/5x4m PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5x4m 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.
+== 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>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+B-cell lymphoma 6 (BCL6) is a transcriptional factor that expresses in lymphocytes and regulates the differentiation and proliferation of lymphocytes. Therefore, BCL6 is a therapeutic target for autoimmune diseases and cancer treatment. This report presents the discovery of BCL6-corepressor interaction inhibitors by using a biophysics-driven fragment-based approach. Using the surface plasmon resonance (SPR)-based fragment screening, we successfully identified fragment 1 (SPR KD = 1200 muM, ligand efficiency (LE) = 0.28), a competitive binder to the natural ligand BCoR peptide. Moreover, we elaborated 1 into the more potent compound 7 (SPR KD = 0.078 muM, LE = 0.37, cell-free protein-protein interaction (PPI) IC50 = 0.48 muM (ELISA), cellular PPI IC50 = 8.6 muM (M2H)) by a structure-based design and structural integration with a second high-throughput screening hit.
-Authors: Sogabe, S., Ida, K., Lane, W., Snell, G.
+Discovery of a B-Cell Lymphoma 6 Protein-Protein Interaction Inhibitor by a Biophysics-Driven Fragment-Based Approach.,Kamada Y, Sakai N, Sogabe S, Ida K, Oki H, Sakamoto K, Lane W, Snell G, Iida M, Imaeda Y, Sakamoto J, Matsui J J Med Chem. 2017 May 11. doi: 10.1021/acs.jmedchem.7b00313. PMID:28471657<ref>PMID:28471657</ref>
-Description: Crystal structure of the BCL6 BTB domain in complex with Compound 1
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
+<div class="pdbe-citations 5x4m" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Ida, K]]
+[[Category: Lane, W]]
 [[Category: Snell, G]]
-[[Category: Lane, W]]
-[[Category: Ida, K]]
 [[Category: Sogabe, S]]
+[[Category: Transcription repressor]]
+[[Category: Transcription-inhibitor complex]]

5x4m: Difference between revisions

Revision as of 13:36, 24 May 2017

Crystal structure of the BCL6 BTB domain in complex with Compound 1

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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