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PDBsum entry 4cbt

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protein ligands metals Protein-protein interface(s) links
Hydrolase PDB id
4cbt
Jmol
Contents
Protein chains
349 a.a.
Ligands
9F4 ×3
Metals
_ZN ×6
Waters ×10
PDB id:
4cbt
Name: Hydrolase
Title: Design, synthesis, and biological evaluation of potent and selective class iia hdac inhibitors as a potential therapy for huntingtons disease
Structure: Histone deacetylase 4. Chain: a, b, c. Fragment: catalytic domain, residues 648-1033. Synonym: hd4, hdac4. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 469008.
Resolution:
3.03Å     R-factor:   0.214     R-free:   0.273
Authors: R.W.Burli,C.A.Luckhurst,O.Aziz,K.L.Matthews,D.Yates,K.A.Lyon M.Beconi,G.Mcallister,P.Breccia,A.J.Stott,S.D.Penrose,M.Wal M.Lamers,P.Leonard,I.Mueller,C.M.Richardson,R.Jarvis,L.Ston S.Hughes,G.Wishart,A.F.Haughan,C.Oconnell,T.Mead,H.Mcneil,J J.Mangette,M.Maillard,V.Beaumont,I.Munoz-Sanjuan,C.Domingue
Key ref: R.W.Bürli et al. (2013). Design, synthesis, and biological evaluation of potent and selective class IIa histone deacetylase (HDAC) inhibitors as a potential therapy for Huntington's disease. J Med Chem, 56, 9934-9954. PubMed id: 24261862 DOI: 10.1021/jm4011884
Date:
16-Oct-13     Release date:   11-Dec-13    
PROCHECK
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 Headers
 References

Protein chains
Pfam   ArchSchema ?
P56524  (HDAC4_HUMAN) -  Histone deacetylase 4
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
1084 a.a.
349 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: E.C.3.5.1.98  - Histone deacetylase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

 

 
DOI no: 10.1021/jm4011884 J Med Chem 56:9934-9954 (2013)
PubMed id: 24261862  
 
 
Design, synthesis, and biological evaluation of potent and selective class IIa histone deacetylase (HDAC) inhibitors as a potential therapy for Huntington's disease.
R.W.Bürli, C.A.Luckhurst, O.Aziz, K.L.Matthews, D.Yates, K.A.Lyons, M.Beconi, G.McAllister, P.Breccia, A.J.Stott, S.D.Penrose, M.Wall, M.Lamers, P.Leonard, I.Müller, C.M.Richardson, R.Jarvis, L.Stones, S.Hughes, G.Wishart, A.F.Haughan, C.O'Connell, T.Mead, H.McNeil, J.Vann, J.Mangette, M.Maillard, V.Beaumont, I.Munoz-Sanjuan, C.Dominguez.
 
  ABSTRACT  
 
Inhibition of class IIa histone deacetylase (HDAC) enzymes have been suggested as a therapeutic strategy for a number of diseases, including Huntington's disease. Catalytic-site small molecule inhibitors of the class IIa HDAC4, -5, -7, and -9 were developed. These trisubstituted diarylcyclopropanehydroxamic acids were designed to exploit a lower pocket that is characteristic for the class IIa HDACs, not present in other HDAC classes. Selected inhibitors were cocrystallized with the catalytic domain of human HDAC4. We describe the first HDAC4 catalytic domain crystal structure in a "closed-loop" form, which in our view represents the biologically relevant conformation. We have demonstrated that these molecules can differentiate class IIa HDACs from class I and class IIb subtypes. They exhibited pharmacokinetic properties that should enable the assessment of their therapeutic benefit in both peripheral and CNS disorders. These selective inhibitors provide a means for evaluating potential efficacy in preclinical models in vivo.