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PDBsum entry 2v5x

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protein ligands metals Protein-protein interface(s) links
Hydrolase PDB id
2v5x
Jmol
Contents
Protein chains
363 a.a. *
Ligands
V5X ×2
Metals
_ZN ×2
__K ×4
Waters ×321
* Residue conservation analysis
PDB id:
2v5x
Name: Hydrolase
Title: Crystal structure of hdac8-inhibitor complex
Structure: Histone deacetylase 8. Chain: a, b. Synonym: hdac8, hd8. Engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562.
Resolution:
2.25Å     R-factor:   0.198     R-free:   0.240
Authors: S.Di Marco,A.Vannini,C.Volpari,P.Gallinari,P.Jones,M.Mattu,A R.Defrancesco,C.Steinkuhler
Key ref:
A.Vannini et al. (2007). Substrate binding to histone deacetylases as shown by the crystal structure of the HDAC8-substrate complex. EMBO Rep, 8, 879-884. PubMed id: 17721440 DOI: 10.1038/sj.embor.7401047
Date:
10-Jul-07     Release date:   04-Sep-07    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
Q9BY41  (HDAC8_HUMAN) -  Histone deacetylase 8
Seq:
Struc:
377 a.a.
363 a.a.*
Key:    PfamA domain  PfamB 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]
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     cytoplasm   5 terms 
  Biological process     histone H3 deacetylation   11 terms 
  Biochemical function     hydrolase activity     11 terms  

 

 
DOI no: 10.1038/sj.embor.7401047 EMBO Rep 8:879-884 (2007)
PubMed id: 17721440  
 
 
Substrate binding to histone deacetylases as shown by the crystal structure of the HDAC8-substrate complex.
A.Vannini, C.Volpari, P.Gallinari, P.Jones, M.Mattu, A.Carfí, R.De Francesco, C.Steinkühler, S.Di Marco.
 
  ABSTRACT  
 
Histone deacetylases (HDACs)-an enzyme family that deacetylates histones and non-histone proteins-are implicated in human diseases such as cancer, and the first-generation of HDAC inhibitors are now in clinical trials. Here, we report the 2.0 A resolution crystal structure of a catalytically inactive HDAC8 active-site mutant, Tyr306Phe, bound to an acetylated peptidic substrate. The structure clarifies the role of active-site residues in the deacetylation reaction and substrate recognition. Notably, the structure shows the unexpected role of a conserved residue at the active-site rim, Asp 101, in positioning the substrate by directly interacting with the peptidic backbone and imposing a constrained cis-conformation. A similar interaction is observed in a new hydroxamate inhibitor-HDAC8 structure that we also solved. The crucial role of Asp 101 in substrate and inhibitor recognition was confirmed by activity and binding assays of wild-type HDAC8 and Asp101Ala, Tyr306Phe and Asp101Ala/Tyr306Phe mutants.
 
  Selected figure(s)  
 
Figure 1.
Figure 1 Structure of the human HDAC8–substrate complex. (A) Ribbon diagram of the two HDAC8–substrate complexes in the asymmetric unit. The substrate and residues involved in the head-to-head packing are shown in a stick representation. Carbon, oxygen and nitrogen for the substrate are green, red and blue, respectively. Zn^2+ and K^+ ions are represented as purple spheres. (B) Enlarged view of the substrate-binding site in the asymmetric unit with the 1.0 -contoured 2F[o]-F[c] electron density map. (C) HDAC8 monomer with the bound substrate. Atoms are coloured as in (A). (D) Enlarged view of the active site. Polar interactions are shown as dashed yellow lines. HDAC, histone deacetylase.
Figure 3.
Figure 3 Comparison of the structure of HDAC8–substrate with that of the HDAC8–hydroxamate inhibitor. (A) View of the substrate-binding site superimposed with the structure of the HDAC8–inhibitor (r.m.s.d.-C , 0.315 Å). Oxygen, nitrogen and carbon of the inhibitor are red, blue and cyan, respectively. Protein is cyan in the HDAC8–inhibitor structure. (B) Molecular surface of the HDAC8–substrate complex at the active-site entrance. Water molecules are shown as red spheres. (C) Molecular surface of the HDAC8–inhibitor complex. HDAC, histone deacetylase.
 
  The above figures are reprinted by permission from Macmillan Publishers Ltd: EMBO Rep (2007, 8, 879-884) copyright 2007.  
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
22885700 M.A.Deardorff, M.Bando, R.Nakato, E.Watrin, T.Itoh, M.Minamino, K.Saitoh, M.Komata, Y.Katou, D.Clark, K.E.Cole, E.De Baere, C.Decroos, N.Di Donato, S.Ernst, L.J.Francey, Y.Gyftodimou, K.Hirashima, M.Hullings, Y.Ishikawa, C.Jaulin, M.Kaur, T.Kiyono, P.M.Lombardi, L.Magnaghi-Jaulin, G.R.Mortier, N.Nozaki, M.B.Petersen, H.Seimiya, V.M.Siu, Y.Suzuki, K.Takagaki, J.J.Wilde, P.J.Willems, C.Prigent, G.Gillessen-Kaesbach, D.W.Christianson, F.J.Kaiser, L.G.Jackson, T.Hirota, I.D.Krantz, and K.Shirahige (2012).
HDAC8 mutations in Cornelia de Lange syndrome affect the cohesin acetylation cycle.
  Nature, 489, 313-317.  
21188173 A.Linares, F.Dalenc, P.Balaguer, N.Boulle, and V.Cavailles (2011).
Manipulating protein acetylation in breast cancer: a promising approach in combination with hormonal therapies?
  J Biomed Biotechnol, 2011, 856985.  
20337574 F.Lonardo, X.Li, A.Kaplun, A.Soubani, S.Sethi, S.Gadgeel, and S.Sheng (2010).
The natural tumor suppressor protein maspin and potential application in non small cell lung cancer.
  Curr Pharm Des, 16, 1877-1881.  
20571512 R.H.Wilting, E.Yanover, M.R.Heideman, H.Jacobs, J.Horner, J.van der Torre, R.A.DePinho, and J.H.Dannenberg (2010).
Overlapping functions of Hdac1 and Hdac2 in cell cycle regulation and haematopoiesis.
  EMBO J, 29, 2586-2597.  
20029090 S.L.Gantt, C.G.Joseph, and C.A.Fierke (2010).
Activation and inhibition of histone deacetylase 8 by monovalent cations.
  J Biol Chem, 285, 6036-6043.  
19349466 A.Bougdour, D.Maubon, P.Baldacci, P.Ortet, O.Bastien, A.Bouillon, J.C.Barale, H.Pelloux, R.Ménard, and M.A.Hakimi (2009).
Drug inhibition of HDAC3 and epigenetic control of differentiation in Apicomplexa parasites.
  J Exp Med, 206, 953-966.  
18603028 B.C.Smith, and J.M.Denu (2009).
Chemical mechanisms of histone lysine and arginine modifications.
  Biochim Biophys Acta, 1789, 45-57.  
19886628 B.He, S.Velaparthi, G.Pieffet, C.Pennington, A.Mahesh, D.L.Holzle, M.Brunsteiner, R.van Breemen, S.Y.Blond, and P.A.Petukhov (2009).
Binding ensemble profiling with photoaffinity labeling (BEProFL) approach: mapping the binding poses of HDAC8 inhibitors.
  J Med Chem, 52, 7003-7013.  
19355989 D.Wang (2009).
Computational studies on the histone deacetylases and the design of selective histone deacetylase inhibitors.
  Curr Top Med Chem, 9, 241-256.  
19821480 P.Galletti, A.Quintavalla, C.Ventrici, G.Giannini, W.Cabri, S.Penco, G.Gallo, S.Vincenti, and D.Giacomini (2009).
Azetidinones as Zinc-Binding Groups to Design Selective HDAC8 Inhibitors.
  ChemMedChem, 4, 1991-2001.  
20161624 R.Wu, P.Hu, S.Wang, Z.Cao, and Y.Zhang (2009).
Flexibility of Catalytic Zinc Coordination in Thermolysin and HDAC8: A Born-Oppenheimer ab initio QM/MM Molecular Dynamics Study.
  J Chem Theory Comput, 6, 337.  
19822520 Y.Luo, W.Jian, D.Stavreva, X.Fu, G.Hager, J.Bungert, S.Huang, and Y.Qiu (2009).
Trans-regulation of histone deacetylase activities through acetylation.
  J Biol Chem, 284, 34901-34910.  
18568164 A.J.Vegas, J.H.Fuller, and A.N.Koehler (2008).
Small-molecule microarrays as tools in ligand discovery.
  Chem Soc Rev, 37, 1385-1394.  
18285338 A.Schuetz, J.Min, A.Allali-Hassani, M.Schapira, M.Shuen, P.Loppnau, R.Mazitschek, N.P.Kwiatkowski, T.A.Lewis, R.L.Maglathin, T.H.McLean, A.Bochkarev, A.N.Plotnikov, M.Vedadi, and C.H.Arrowsmith (2008).
Human HDAC7 harbors a class IIa histone deacetylase-specific zinc binding motif and cryptic deacetylase activity.
  J Biol Chem, 283, 11355-11363.
PDB codes: 3c0y 3c0z 3c10
18360740 D.P.Dowling, L.Di Costanzo, H.A.Gennadios, and D.W.Christianson (2008).
Evolution of the arginase fold and functional diversity.
  Cell Mol Life Sci, 65, 2039-2055.  
19053282 D.P.Dowling, S.L.Gantt, S.G.Gattis, C.A.Fierke, and D.W.Christianson (2008).
Structural studies of human histone deacetylase 8 and its site-specific variants complexed with substrate and inhibitors.
  Biochemistry, 47, 13554-13563.
PDB codes: 3ew8 3ewf 3ezp 3ezt 3f06 3f07 3f0r
18614528 M.J.Bottomley, P.Lo Surdo, P.Di Giovine, A.Cirillo, R.Scarpelli, F.Ferrigno, P.Jones, P.Neddermann, R.De Francesco, C.Steinkühler, P.Gallinari, and A.Carfí (2008).
Structural and functional analysis of the human HDAC4 catalytic domain reveals a regulatory structural zinc-binding domain.
  J Biol Chem, 283, 26694-26704.
PDB codes: 2vqj 2vqm 2vqo 2vqq 2vqv 2vqw
18470998 Z.A.Gurard-Levin, and M.Mrksich (2008).
The activity of HDAC8 depends on local and distal sequences of its peptide substrates.
  Biochemistry, 47, 6242-6250.  
17984971 S.Lall (2007).
Primers on chromatin.
  Nat Struct Mol Biol, 14, 1110-1115.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.