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PDBsum entry 4cp3
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Immune system
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PDB id
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4cp3
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PDB id:
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| Name: |
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Immune system
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Title:
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The structure of bcl6 btb (poz) domain in complex with the ansamycin antibiotic rifabutin.
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Structure:
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B-cell lymphoma 6 protein. Chain: a, b. Fragment: btb domain, residues 9-128. Synonym: bcl-6, b-cell lymphoma 5 protein, bcl-5, protein laz-3, zinc finger and btb domain-containing protein 27, zinc finger protein 51. Engineered: yes. Mutation: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 469008. Expression_system_variant: rosetta.
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Resolution:
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2.30Å
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R-factor:
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0.202
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R-free:
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0.269
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Authors:
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S.E.Evans,L.Fairall,B.T.Goult,A.G.Jamieson,P.K.Ferrigno,R.Ford, S.D.Wagner,J.W.R.Schwabe
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Key ref:
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S.E.Evans
et al.
(2014).
The ansamycin antibiotic, rifamycin SV, inhibits BCL6 transcriptional repression and forms a complex with the BCL6-BTB/POZ domain.
Plos One,
9,
e90889.
PubMed id:
DOI:
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Date:
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31-Jan-14
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Release date:
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19-Mar-14
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PROCHECK
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Headers
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References
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P41182
(BCL6_HUMAN) -
B-cell lymphoma 6 protein from Homo sapiens
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Seq:
Struc:
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706 a.a.
122 a.a.*
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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*
PDB and UniProt seqs differ
at 4 residue positions (black
crosses)
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DOI no:
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Plos One
9:e90889
(2014)
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PubMed id:
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The ansamycin antibiotic, rifamycin SV, inhibits BCL6 transcriptional repression and forms a complex with the BCL6-BTB/POZ domain.
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S.E.Evans,
B.T.Goult,
L.Fairall,
A.G.Jamieson,
P.Ko Ferrigno,
R.Ford,
J.W.Schwabe,
S.D.Wagner.
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ABSTRACT
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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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Links
