PDBsum entry 4ly1

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protein ligands metals Protein-protein interface(s) links
Hydrolase/hydrolase inhibitor PDB id
Protein chains
368 a.a.
PG4 ×8
20Y ×3
_ZN ×3
_CA ×3
_NA ×3
Waters ×846
PDB id:
Name: Hydrolase/hydrolase inhibitor
Title: Structure of human hdac2 in complex with inhibitor 4-(acetyl [2-amino-5-(thiophen-2-yl)phenyl]benzamide
Structure: Histone deacetylase 2. Chain: a, b, c. Fragment: core domain (unp residues 8-376). Synonym: hd2. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: hdac2. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108
1.57Å     R-factor:   0.170     R-free:   0.187
Authors: R.Fong,P.J.Lupardus
Key ref: B.E.Lauffer et al. (2013). Histone deacetylase (HDAC) inhibitor kinetic rate constants correlate with cellular histone acetylation but not transcription and cell viability. J Biol Chem, 288, 26926-26943. PubMed id: 23897821 DOI: 10.1074/jbc.M113.490706
30-Jul-13     Release date:   21-Aug-13    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
Q92769  (HDAC2_HUMAN) -  Histone deacetylase 2
488 a.a.
368 a.a.
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.  - Histone deacetylase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     histone deacetylation   1 term 
  Biochemical function     histone deacetylase activity     1 term  


DOI no: 10.1074/jbc.M113.490706 J Biol Chem 288:26926-26943 (2013)
PubMed id: 23897821  
Histone deacetylase (HDAC) inhibitor kinetic rate constants correlate with cellular histone acetylation but not transcription and cell viability.
B.E.Lauffer, R.Mintzer, R.Fong, S.Mukund, C.Tam, I.Zilberleyb, B.Flicke, A.Ritscher, G.Fedorowicz, R.Vallero, D.F.Ortwine, J.Gunzner, Z.Modrusan, L.Neumann, C.M.Koth, P.J.Lupardus, J.S.Kaminker, C.E.Heise, P.Steiner.
Histone deacetylases (HDACs) are critical in the control of gene expression, and dysregulation of their activity has been implicated in a broad range of diseases, including cancer, cardiovascular, and neurological diseases. HDAC inhibitors (HDACi) employing different zinc chelating functionalities such as hydroxamic acids and benzamides have shown promising results in cancer therapy. Although it has also been suggested that HDACi with increased isozyme selectivity and potency may broaden their clinical utility and minimize side effects, the translation of this idea to the clinic remains to be investigated. Moreover, a detailed understanding of how HDACi with different pharmacological properties affect biological functions in vitro and in vivo is still missing. Here, we show that a panel of benzamide-containing HDACi are slow tight-binding inhibitors with long residence times unlike the hydroxamate-containing HDACi vorinostat and trichostatin-A. Characterization of changes in H2BK5 and H4K14 acetylation following HDACi treatment in the neuroblastoma cell line SH-SY5Y revealed that the timing and magnitude of histone acetylation mirrored both the association and dissociation kinetic rates of the inhibitors. In contrast, cell viability and microarray gene expression analysis indicated that cell death induction and changes in transcriptional regulation do not correlate with the dissociation kinetic rates of the HDACi. Therefore, our study suggests that determining how the selective and kinetic inhibition properties of HDACi affect cell function will help to evaluate their therapeutic utility.