Target Information
Target General Information | Top | |||||
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Target ID |
T43548
(Former ID: TTDI01407)
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Target Name |
B-cell lymphoma 6 protein (BCL-6)
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Synonyms |
Zinc finger protein 51; Zinc finger and BTB domain-containing protein 27; ZNF51; ZBTB27; Protein LAZ-3; LAZ3; BCL5; BCL-6; BCL-5; B-cell lymphoma 5 protein
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Gene Name |
BCL6
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Target Type |
Literature-reported target
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[1] | ||||
Function |
Transcriptional repressor mainly required for germinal center (GC) formation and antibody affinity maturation which has different mechanisms of action specific to the lineage and biological functions. Forms complexes with different corepressors and histone deacetylases to repress the transcriptional expression of different subsets of target genes. Represses its target genes by binding directly to the DNA sequence 5'-TTCCTAGAA-3' (BCL6-binding site) or indirectly by repressing the transcriptional activity of transcription factors. In GC B-cells, represses genes that function in differentiation, inflammation, apoptosis and cell cycle control, also autoregulates its transcriptional expression and up-regulates, indirectly, the expression of some genes important for GC reactions, such as AICDA, through the repression of microRNAs expression, like miR155. An important function is to allow GC B-cells to proliferate very rapidly in response to T-cell dependent antigens and tolerate the physiological DNA breaks required for immunglobulin class switch recombination and somatic hypermutation without inducing a p53/TP53-dependent apoptotic response. In follicular helper CD4(+) T-cells (T(FH) cells), promotes the expression of T(FH)-related genes but inhibits the differentiation of T(H)1, T(H)2 and T(H)17 cells. Also required for the establishment and maintenance of immunological memory for both T- and B-cells. Suppresses macrophage proliferation through competition with STAT5 for STAT-binding motifs binding on certain target genes, such as CCL2 and CCND2. In response to genotoxic stress, controls cell cycle arrest in GC B-cells in both p53/TP53-dependedent and -independent manners. Besides, also controls neurogenesis through the alteration of the composition of NOTCH-dependent transcriptional complexes at selective NOTCH targets, such as HES5, including the recruitment of the deacetylase SIRT1 and resulting in an epigenetic silencing leading to neuronal differentiation.
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UniProt ID | ||||||
Sequence |
MASPADSCIQFTRHASDVLLNLNRLRSRDILTDVVIVVSREQFRAHKTVLMACSGLFYSI
FTDQLKCNLSVINLDPEINPEGFCILLDFMYTSRLNLREGNIMAVMATAMYLQMEHVVDT CRKFIKASEAEMVSAIKPPREEFLNSRMLMPQDIMAYRGREVVENNLPLRSAPGCESRAF APSLYSGLSTPPASYSMYSHLPVSSLLFSDEEFRDVRMPVANPFPKERALPCDSARPVPG EYSRPTLEVSPNVCHSNIYSPKETIPEEARSDMHYSVAEGLKPAAPSARNAPYFPCDKAS KEEERPSSEDEIALHFEPPNAPLNRKGLVSPQSPQKSDCQPNSPTESCSSKNACILQASG SPPAKSPTDPKACNWKKYKFIVLNSLNQNAKPEGPEQAELGRLSPRAYTAPPACQPPMEP ENLDLQSPTKLSASGEDSTIPQASRLNNIVNRSMTGSPRSSSESHSPLYMHPPKCTSCGS QSPQHAEMCLHTAGPTFPEEMGETQSEYSDSSCENGAFFCNECDCRFSEEASLKRHTLQT HSDKPYKCDRCQASFRYKGNLASHKTVHTGEKPYRCNICGAQFNRPANLKTHTRIHSGEK PYKCETCGARFVQVAHLRAHVLIHTGEKPYPCEICGTRFRHLQTLKSHLRIHTGEKPYHC EKCNLHFRHKSQLRLHLRQKHGAITNTKVQYRVSATDLPPELPKAC Click to Show/Hide
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3D Structure | Click to Show 3D Structure of This Target | AlphaFold |
Cell-based Target Expression Variations | Top | |||||
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Cell-based Target Expression Variations |
Drug Binding Sites of Target | Top | |||||
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Ligand Name: PF-562271 | Ligand Info | |||||
Structure Description | Crystal structure of the BCL6 BTB domain in complex with Compound 5 | PDB:5X4O | ||||
Method | X-ray diffraction | Resolution | 2.05 Å | Mutation | No | [2] |
PDB Sequence |
LYFQGADSCI
9 QFTRHASDVL19 LNLNRLRSRD29 ILTDVVIVVS39 REQFRAHKTV49 LMACSGLFYS 59 IFTDQLKCNL69 SVINLDPEIN79 PEGFCILLDF89 MYTSRLNLRE99 GNIMAVMATA 109 MYLQMEHVVD119 TCRKFIKASE129
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Ligand Name: 5-[[5-chloranyl-2-[(2~{S},6~{R})-2,6-dimethylmorpholin-4-yl]pyrimidin-4-yl]amino]-1-methyl-3-(3-methyl-3-oxidanyl-butyl)benzimidazol-2-one | Ligand Info | |||||
Structure Description | Crystal structure of human BCL6 BTB domain in complex with compound 25a | PDB:6TOL | ||||
Method | X-ray diffraction | Resolution | 1.64 Å | Mutation | No | [3] |
PDB Sequence |
NLYFQGADSC
8 IQFTRHASDV18 LLNLNRLRSR28 DILTDVVIVV38 SREQFRAHKT48 VLMACSGLFY 58 SIFTDQLKCN68 LSVINLDPEI78 NPEGFCILLD88 FMYTSRLNLR98 EGNIMAVMAT 108 AMYLQMEHVV118 DTCRKFIKAS128 E
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Click to View More Binding Site Information of This Target with Different Ligands |
Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Tissue Distribution
of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.
The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects
(Nat Rev Drug Discov, 20: 64-81, 2021).
Human Pathway Affiliation
of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.
Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes
(Pharmacol Rev, 58: 259-279, 2006).
Biological Network Descriptors
of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.
The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information
(Front Pharmacol, 9, 1245, 2018;
Curr Opin Struct Biol. 44:134-142, 2017).
Human Similarity Proteins
Human Tissue Distribution
Human Pathway Affiliation
Biological Network Descriptors
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Protein Name | Pfam ID | Percentage of Identity (%) | E value |
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Zinc finger protein 335 (ZNF335) | 28.794 (74/257) | 6.03E-24 |
Note:
If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.
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KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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FoxO signaling pathway | hsa04068 | Affiliated Target |
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Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy |
Degree | 24 | Degree centrality | 2.58E-03 | Betweenness centrality | 1.97E-03 |
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Closeness centrality | 2.54E-01 | Radiality | 1.44E+01 | Clustering coefficient | 1.41E-01 |
Neighborhood connectivity | 5.30E+01 | Topological coefficient | 6.73E-02 | Eccentricity | 11 |
Download | Click to Download the Full PPI Network of This Target | ||||
Chemical Structure based Activity Landscape of Target | Top |
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Target Poor or Non Binders | Top | |||||
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Target Poor or Non Binders |
References | Top | |||||
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REF 1 | Homoharringtonine suppresses imatinib resistance via the Bcl-6/p53 pathway in chronic myeloid leukemia cell lines. Oncotarget. 2017 Jun 6;8(23):37594-37604. | |||||
REF 2 | Discovery of a B-Cell Lymphoma 6 Protein-Protein Interaction Inhibitor by a Biophysics-Driven Fragment-Based Approach. J Med Chem. 2017 May 25;60(10):4358-4368. | |||||
REF 3 | Achieving In Vivo Target Depletion through the Discovery and Optimization of Benzimidazolone BCL6 Degraders. J Med Chem. 2020 Apr 23;63(8):4047-4068. |
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