4CP3
The structure of BCL6 BTB (POZ) domain in complex with the ansamycin antibiotic rifabutin.
Summary for 4CP3
| Entry DOI | 10.2210/pdb4cp3/pdb |
| Descriptor | B-CELL LYMPHOMA 6 PROTEIN, RIFABUTIN (3 entities in total) |
| Functional Keywords | immune system, btb/poz, transcriptional repressor, rifamycin, antibiotic, smrt, inhibitor |
| Biological source | HOMO SAPIENS (HUMAN) |
| Cellular location | Nucleus: P41182 |
| Total number of polymer chains | 2 |
| Total formula weight | 29304.09 |
| Authors | Evans, S.E.,Fairall, L.,Goult, B.T.,Jamieson, A.G.,Ferrigno, P.K.,Ford, R.,Wagner, S.D.,Schwabe, J.W.R. (deposition date: 2014-01-31, release date: 2014-03-19, Last modification date: 2023-12-20) |
| Primary citation | Evans, S.E.,Goult, B.T.,Fairall, L.,Jamieson, A.G.,Ko Ferrigno, P.,Ford, R.,Schwabe, J.W.R.,Wagner, S.D. The Ansamycin Antibiotic, Rifamycin Sv, Inhibits Bcl6 Transcriptional Repression and Forms a Complex with the Bcl6-Btb/Poz Domain. Plos One, 9:90889-, 2014 Cited by PubMed 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. PubMed: 24595451DOI: 10.1371/JOURNAL.PONE.0090889 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.3 Å) |
Structure validation
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