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PDBsum entry 4tu6
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Gene regulation
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PDB id
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4tu6
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PDB id:
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| Name: |
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Gene regulation
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Title:
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Crystal structure of apo atad2a bromodomain with n1064 alternate conformation
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Structure:
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Atpase family aaa domain-containing protein 2. Chain: a, b, c, d. Fragment: bromodomain (unp residues 981-1108). Synonym: aaa nuclear coregulator cancer-associated protein,ancca. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: atad2, l16, pro2000. Expressed in: escherichia coli. Expression_system_taxid: 469008.
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Resolution:
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2.27Å
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R-factor:
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0.192
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R-free:
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0.248
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Authors:
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G.Poncet-Montange,Y.Zhan,J.Bardenhagen,A.Petrocchi,E.Leo,X.Shi,G.Lee, P.Leonard,M.Geck Do,M.Cardozo,W.Palmer,J.Andersen,P.Jones,J.Ladbury
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Key ref:
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G.Poncet-Montange
et al.
(2015).
Observed bromodomain flexibility reveals histone peptide- and small molecule ligand-compatible forms of ATAD2.
Biochem J,
466,
337-346.
PubMed id:
DOI:
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Date:
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23-Jun-14
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Release date:
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24-Dec-14
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PROCHECK
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Headers
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References
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Q6PL18
(ATAD2_HUMAN) -
ATPase family AAA domain-containing protein 2 from Homo sapiens
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Seq:
Struc:
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1390 a.a.
130 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 2 residue positions (black
crosses)
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DOI no:
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Biochem J
466:337-346
(2015)
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PubMed id:
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Observed bromodomain flexibility reveals histone peptide- and small molecule ligand-compatible forms of ATAD2.
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G.Poncet-Montange,
Y.Zhan,
J.P.Bardenhagen,
A.Petrocchi,
E.Leo,
X.Shi,
G.R.Lee,
P.G.Leonard,
M.K.Geck Do,
M.G.Cardozo,
J.N.Andersen,
W.S.Palmer,
P.Jones,
J.E.Ladbury.
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ABSTRACT
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Preventing histone recognition by bromodomains emerges as an attractive
therapeutic approach in cancer. Overexpression of ATAD2 (ATPase family AAA
domain-containing 2 isoform A) in cancer cells is associated with poor prognosis
making the bromodomain of ATAD2 a promising epigenetic therapeutic target. In
the development of an in vitro assay and identification of small molecule
ligands, we conducted structure-guided studies which revealed a conformationally
flexible ATAD2 bromodomain. Structural studies on apo-, peptide-and small
molecule-ATAD2 complexes (by co-crystallization) revealed that the bromodomain
adopts a 'closed', histone-compatible conformation and a more 'open'
ligand-compatible conformation of the binding site respectively. An unexpected
conformational change of the conserved asparagine residue plays an important
role in driving the peptide-binding conformation remodelling. We also identified
dimethylisoxazole-containing ligands as ATAD2 binders which aided in the
validation of the in vitro screen and in the analysis of these conformational
studies.
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Links
