2V5W

Crystal structure of HDAC8-substrate complex


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.230 
  • R-Value Work: 0.176 
  • R-Value Observed: 0.179 

wwPDB Validation   3D Report Full Report


This is version 1.4 of the entry. See complete history


Literature

Substrate Binding to Histone Deacetylases as Revealed by Crystal Structure of Hdac8-Substrate Complex

Vannini, A.Volpari, C.Gallinari, P.Jones, P.Mattu, M.Carfi, A.Defrancesco, R.Steinkuhler, C.Di Marco, S.

(2007) EMBO Rep 8: 879

  • DOI: https://doi.org/10.1038/sj.embor.7401047
  • Primary Citation of Related Structures:  
    2V5W, 2V5X

  • PubMed 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.


  • Organizational Affiliation

    Istituto di Ricerche di Biologia Molecolare P. Angeletti, Via Pontina Km 30.600, 00040 Pomezia, Rome, Italy.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
HISTONE DEACETYLASE 8
A, B
388Homo sapiensMutation(s): 1 
UniProt & NIH Common Fund Data Resources
Find proteins for Q9BY41 (Homo sapiens)
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Go to UniProtKB:  Q9BY41
PHAROS:  Q9BY41
GTEx:  ENSG00000147099 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9BY41
Sequence Annotations
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  • Reference Sequence

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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
GLYCYL-GLYCYL-GLYCINEC [auth G]3synthetic constructMutation(s): 0 
Sequence Annotations
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  • Reference Sequence

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Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
PEPTIDIC SUBSTRATED [auth I],
E [auth L]
6synthetic constructMutation(s): 0 
UniProt & NIH Common Fund Data Resources
Find proteins for P04637 (Homo sapiens)
Explore P04637 
Go to UniProtKB:  P04637
PHAROS:  P04637
GTEx:  ENSG00000141510 
Entity Groups  
UniProt GroupP04637
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.230 
  • R-Value Work: 0.176 
  • R-Value Observed: 0.179 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 52.304α = 90
b = 151.801β = 117.02
c = 57.552γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
MOSFLMdata reduction
SCALAdata scaling
AMoREphasing

Structure Validation

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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2007-09-04
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Atomic model, Database references, Derived calculations, Non-polymer description, Structure summary, Version format compliance
  • Version 1.2: 2016-12-21
    Changes: Source and taxonomy
  • Version 1.3: 2019-05-29
    Changes: Data collection, Derived calculations, Experimental preparation, Other
  • Version 1.4: 2023-12-13
    Changes: Data collection, Database references, Derived calculations, Other, Refinement description