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The Ansamycin Antibiotic, Rifamycin SV, Inhibits BCL6 Transcriptional Repression and Forms a Complex with the BCL6-BTB/POZ Domain

DOI: 10.1371/journal.pone.0090889 DOI Help
PMID: 24595451 PMID Help

Authors: Sian Evans (University of Leicester) , Benjamin T. Goult (University of Leicester) , Louise Fairall (University of Leicester) , Andrew G. Jamieson (University of Leicester) , Paul Ko Ferrigno (University of Leeds) , Robert Ford (University of Leeds) , John W. R. Schwabe (University of Leicester) , Simon D. Wagner (University of Leicester) , Javier Marcelo Di Noia (University of Leicester)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Plos One , VOL 9 (3)

State: Published (Approved)
Published: March 2014
Diamond Proposal Number(s): 8359

Open Access Open Access

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.

Journal Keywords: Crystallography ; X-Ray ; DNA-Binding; HEK293; Humans ; Models ; Molecular ; Nuclear; Protein; Tertiary ; Repressor; Rifabutin ; Rifamycins ; Transcription ; Genetic

Subject Areas: Biology and Bio-materials


Instruments: I24-Microfocus Macromolecular Crystallography

Added On: 19/03/2014 15:53

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