Evans, Sian E, Goult, Benjamin T 
ORCID: 0000-0002-3438-2807, Fairall, Louise ORCID: 0000-0001-9456-3047, Jamieson, Andrew G ORCID: 0000-0003-1726-7353, Ko Ferrigno, Paul ORCID: 0000-0002-5922-4100, Ford, Robert, Schwabe, John WR ORCID: 0000-0003-2865-4383 and Wagner, Simon D ORCID: 0000-0002-8914-0370
(2014)
The ansamycin antibiotic, rifamycin SV, inhibits BCL6 transcriptional repression and forms a complex with the BCL6-BTB/POZ domain.
PloS one, 9 (3).
e90889-.
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The ansamycin antibiotic, rifamycin SV, inhibits BCL6 transcriptional repression and forms a complex with the BCL6-BTBPOZ do.pdf - Open Access published version Download (3MB) | Preview |
Abstract
BCL6 is a transcriptional repressor that is over-expressed due to chromosomal translocations, or other abnormalities, in ∼40% of diffuse large B-cell lymphoma. BCL6 interacts with co-repressor, SMRT, and this is essential for its role in lymphomas. Peptide or small molecule inhibitors, which prevent the association of SMRT with BCL6, inhibit transcriptional repression and cause apoptosis of lymphoma cells in vitro and in vivo. In order to discover compounds, which have the potential to be developed into BCL6 inhibitors, we screened a natural product library. The ansamycin antibiotic, rifamycin SV, inhibited BCL6 transcriptional repression and NMR spectroscopy confirmed a direct interaction between rifamycin SV and BCL6. To further determine the characteristics of compounds binding to BCL6-POZ we analyzed four other members of this family and showed that rifabutin, bound most strongly. An X-ray crystal structure of the rifabutin-BCL6 complex revealed that rifabutin occupies a partly non-polar pocket making interactions with tyrosine58, asparagine21 and arginine24 of the BCL6-POZ domain. Importantly these residues are also important for the interaction of BLC6 with SMRT. This work demonstrates a unique approach to developing a structure activity relationship for a compound that will form the basis of a therapeutically useful BCL6 inhibitor.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | Humans, Rifamycins, Rifabutin, DNA-Binding Proteins, Repressor Proteins, Anti-Bacterial Agents, Crystallography, X-Ray, Transcription, Genetic, Protein Structure, Tertiary, Models, Molecular, Proto-Oncogene Proteins c-bcl-6, Nuclear Receptor Co-Repressor 2, HEK293 Cells, Protein Interaction Maps |
| Divisions: | Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 13 Mar 2024 09:45 |
| Last Modified: | 13 Mar 2024 09:45 |
| DOI: | 10.1371/journal.pone.0090889 |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3179334 |
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