The ansamycin antibiotic, rifamycin SV, inhibits BCL6 transcriptional repression and forms a complex with the BCL6-BTB/POZ domain.
The ansamycin antibiotic, rifamycin SV, inhibits BCL6 transcriptional repression and forms a complex with the BCL6-BTB/POZ domain.
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DOI：
10.1371/journal.pone.0090889
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Wagner SD
中科院分区：
文献类型：
--
作者：
Evans SE;Goult BT;Fairall L;Jamieson AG;Ko Ferrigno P;Ford R;Schwabe JW;Wagner SD
BCL 6是一种转录抑制因子，在大约40%的弥漫性大B细胞淋巴瘤中由于染色体易位或其他异常而过度表达。BCL 6与辅阻遏物SMRT相互作用，这对其在淋巴瘤中的作用至关重要。阻止SMRT与BCL 6结合的肽或小分子抑制剂在体外和体内抑制转录抑制并引起淋巴瘤细胞凋亡。为了发现具有开发为BCL 6抑制剂潜力的化合物，我们筛选了天然产物库。安莎霉素抗生素利福霉素SV抑制BCL 6转录抑制，NMR光谱证实利福霉素SV和BCL 6之间的直接相互作用。为了进一步确定与BCL 6-POZ结合的化合物的特征，我们分析了该家族的其他四个成员，并显示利福布雷定结合最强。利福布汀-BCL 6复合物的X射线晶体结构显示利福布汀占据部分非极性口袋，与BCL 6-POZ结构域的酪氨酸58、天冬酰胺21和天冬氨酸24相互作用。重要的是，这些残基对于BLC 6与SMRT的相互作用也很重要。这项工作展示了一种独特的方法来开发一种化合物的结构活性关系，该化合物将形成治疗上有用的BCL 6抑制剂的基础。
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.
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影响因子：
29
作者：
Barish GD;Yu RT;Karunasiri MS;Becerra D;Kim J;Tseng TW;Tai LJ;Leblanc M;Diehl C;Cerchietti L;Miller YI;Witztum JL;Melnick AM;Dent AL;Tangirala RK;Evans RM
通讯作者：
Evans RM
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16.8
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影响因子：
20.3
作者：
Cerchietti, Leandro C.;Yang, Shao Ning;Melnick, Ari
通讯作者：
Melnick, Ari
影响因子：
158.5
作者：
Lossos, IS;Czerwinski, DK;Levy, R
通讯作者：
Levy, R
影响因子：
64.8
作者：
Alizadeh, AA;Eisen, MB;Staudt, LM
通讯作者：
Staudt, LM