5x4m

From Proteopedia

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

PDB ID 5x4m

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Structural highlights

5x4m is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.65Å
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

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:http://dx.doi.org/10.1021/acs.jmedchem.7b00313

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

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5x4m

From Proteopedia

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

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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