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PDBsum entry 4ir3

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protein ligands links
Transcription PDB id
4ir3
Jmol PyMol
Contents
Protein chain
116 a.a.
Ligands
EDO ×3
GOL ×2
1FK
Waters ×146
PDB id:
4ir3
Name: Transcription
Title: Crystal structure of the bromodomain of human baz2b in compl [7-amino-1-(pyrimidin-2-yl)indolizin-3-yl]ethanone (gsk2833
Structure: Bromodomain adjacent to zinc finger domain protei chain: a. Fragment: bromodomain (residues 2054-2168). Synonym: hwalp4. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: baz2b, kiaa1476. Expressed in: escherichia coli. Expression_system_taxid: 469008.
Resolution:
2.00Å     R-factor:   0.211     R-free:   0.245
Authors: A.Chaikuad,I.Felletar,C.W.Chung,D.Drewry,P.Chen,P.Filippakop O.Fedorov,T.Krojer,F.Von Delft,C.H.Arrowsmith,A.M.Edwards,C S.Knapp,Structural Genomics Consortium (Sgc)
Key ref: P.Chen et al. (2016). Discovery and Characterization of GSK2801, a Selective Chemical Probe for the Bromodomains BAZ2A and BAZ2B. J Med Chem, 59, 1410-1424. PubMed id: 25799074 DOI: 10.1021/acs.jmedchem.5b00209
Date:
14-Jan-13     Release date:   23-Jan-13    
PROCHECK
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 Headers
 References

Protein chain
Pfam   ArchSchema ?
Q9UIF8  (BAZ2B_HUMAN) -  Bromodomain adjacent to zinc finger domain protein 2B
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
2168 a.a.
116 a.a.*
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 2 residue positions (black crosses)

 

 
DOI no: 10.1021/acs.jmedchem.5b00209 J Med Chem 59:1410-1424 (2016)
PubMed id: 25799074  
 
 
Discovery and Characterization of GSK2801, a Selective Chemical Probe for the Bromodomains BAZ2A and BAZ2B.
P.Chen, A.Chaikuad, P.Bamborough, M.Bantscheff, C.Bountra, C.W.Chung, O.Fedorov, P.Grandi, D.Jung, R.Lesniak, M.Lindon, S.Müller, M.Philpott, R.Prinjha, C.Rogers, C.Selenski, C.Tallant, T.Werner, T.M.Willson, S.Knapp, D.H.Drewry.
 
  ABSTRACT  
 
Bromodomains are acetyl-lysine specific protein interaction domains that have recently emerged as a new target class for the development of inhibitors that modulate gene transcription. The two closely related bromodomain containing proteins BAZ2A and BAZ2B constitute the central scaffolding protein of the nucleolar remodeling complex (NoRC) that regulates the expression of noncoding RNAs. However, BAZ2 bromodomains have low predicted druggability and so far no selective inhibitors have been published. Here we report the development of GSK2801, a potent, selective and cell active acetyl-lysine competitive inhibitor of BAZ2A and BAZ2B bromodomains as well as the inactive control compound GSK8573. GSK2801 binds to BAZ2 bromodomains with dissociation constants (KD) of 136 and 257 nM for BAZ2B and BAZ2A, respectively. Crystal structures demonstrated a canonical acetyl-lysine competitive binding mode. Cellular activity was demonstrated using fluorescent recovery after photobleaching (FRAP) monitoring displacement of GFP-BAZ2A from acetylated chromatin. A pharmacokinetic study in mice showed that GSK2801 had reasonable in vivo exposure after oral dosing, with modest clearance and reasonable plasma stability. Thus, GSK2801 represents a versatile tool compound for cellular and in vivo studies to understand the role of BAZ2 bromodomains in chromatin biology.
 

 

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