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PDBsum entry 5a7c
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DNA binding protein
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PDB id
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5a7c
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PDB id:
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| Name: |
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DNA binding protein
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Title:
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Crystal structure of the second bromodomain of human brd3 in complex with compound
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Structure:
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Bromodomain-containing protein 3. Chain: a, b, c, d. Fragment: bromo 2 domain, residues 306-416. Synonym: ring3-like protein. Engineered: 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: t1r prare2.
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Resolution:
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1.90Å
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R-factor:
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0.229
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R-free:
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0.256
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Authors:
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M.Welin,R.Kimbung,C.Diehl,M.Hakansson,D.T.Logan,B.Walse
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Key ref:
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L.M.Nilsson
et al.
(2016).
Cancer Differentiating Agent Hexamethylene Bisacetamide Inhibits BET Bromodomain Proteins.
Cancer Res,
76,
2376-2383.
PubMed id:
DOI:
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Date:
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03-Jul-15
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Release date:
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16-Mar-16
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PROCHECK
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Headers
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References
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Q15059
(BRD3_HUMAN) -
Bromodomain-containing protein 3 from Homo sapiens
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Seq:
Struc:
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726 a.a.
112 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 1 residue position (black
cross)
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DOI no:
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Cancer Res
76:2376-2383
(2016)
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PubMed id:
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Cancer Differentiating Agent Hexamethylene Bisacetamide Inhibits BET Bromodomain Proteins.
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L.M.Nilsson,
L.C.Green,
S.V.Muralidharan,
D.Demir,
M.Welin,
J.Bhadury,
D.T.Logan,
B.Walse,
J.A.Nilsson.
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ABSTRACT
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Agents that trigger cell differentiation are highly efficacious in treating
certain cancers, but such approaches are not generally effective in most
malignancies. Compounds such as DMSO and hexamethylene bisacetamide (HMBA) have
been used to induce differentiation in experimental systems, but their
mechanisms of action and potential range of uses on that basis have not been
developed. Here, we show that HMBA, a compound first tested in the oncology
clinic over 25 years ago, acts as a selective bromodomain inhibitor. Biochemical
and structural studies revealed an affinity of HMBA for the second bromodomain
of BET proteins. Accordingly, both HMBA and the prototype BET inhibitor JQ1
induced differentiation of mouse erythroleukemia cells. As expected of a BET
inhibitor, HMBA displaced BET proteins from chromatin, caused massive
transcriptional changes, and triggered cell-cycle arrest and apoptosis in
Myc-induced B-cell lymphoma cells. Furthermore, HMBA exerted anticancer effects
in vivo in mouse models of Myc-driven B-cell lymphoma. This study illuminates
the function of an early anticancer agent and suggests an intersection with
ongoing clinical trials of BET inhibitor, with several implications for
predicting patient selection and response rates to this therapy and starting
points for generating BD2-selective BET inhibitors. Cancer Res; 76(8); 2376-83.
©2016 AACR.
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Links
