7JVV

Crystal structure of human histone deacetylase 8 (HDAC8) E66D/Y306F double mutation complexed with a tetrapeptide substrate


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.84 Å
  • R-Value Free: 0.197 
  • R-Value Work: 0.164 
  • R-Value Observed: 0.166 

Starting Model: experimental
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wwPDB Validation   3D Report Full Report


This is version 1.3 of the entry. See complete history


Literature

Structural analysis of histone deacetylase 8 mutants associated with Cornelia de Lange Syndrome spectrum disorders.

Osko, J.D.Porter, N.J.Decroos, C.Lee, M.S.Watson, P.R.Raible, S.E.Krantz, I.D.Deardorff, M.A.Christianson, D.W.

(2020) J Struct Biol 213: 107681-107681

  • DOI: https://doi.org/10.1016/j.jsb.2020.107681
  • Primary Citation of Related Structures:  
    7JVU, 7JVV, 7JVW

  • PubMed Abstract: 

    Cornelia de Lange Syndrome (CdLS) and associated spectrum disorders are characterized by one or more congenital anomalies including distinctive facial features, upper limb abnormalities, intellectual disability, and other symptoms. The molecular genetic basis of CdLS is linked to defects in cohesin, a protein complex that functions in sister chromatid cohesion, chromatin organization, and transcriptional regulation. Histone deacetylase 8 (HDAC8) plays an important role in cohesin function by catalyzing the deacetylation of SMC3, which is required for efficient recycling of the cohesin complex. Missense mutations in HDAC8 have been identified in children diagnosed with CdLS spectrum disorders, and here we outline structure-function relationships for four of these mutations. Specifically, we report the 1.50 Å-resolution structure of the I45T HDAC8-suberoylanilide hydroxamic acid complex, the 1.84 Å-resolution structure of E66D/Y306F HDAC8 complexed with a peptide assay substrate, and the 2.40 Å-resolution structure of G320R HDAC8 complexed with the inhibitor M344. Additionally, we present a computationally generated model of D176G HDAC8. These structures illuminate new structure-function relationships for HDAC8 and highlight the importance of long-range interactions in the protein scaffold that can influence catalytic function.


  • Organizational Affiliation

    Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, 231 South 34(th) Street, Philadelphia, PA 19104-6323, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Histone deacetylase 8
A, B
389Homo sapiensMutation(s): 2 
Gene Names: HDAC8HDACL1CDA07
EC: 3.5.1.98 (PDB Primary Data), 3.5.1 (UniProt)
UniProt & NIH Common Fund Data Resources
Find proteins for Q9BY41 (Homo sapiens)
Explore Q9BY41 
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

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
ACE-ARG-HIS-ALY-ALY-MCM
C, D
6Homo sapiensMutation(s): 0 
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
GOL
Query on GOL

Download Ideal Coordinates CCD File 
K [auth A],
R [auth B]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
ZN
Query on ZN

Download Ideal Coordinates CCD File 
H [auth A],
O [auth B]
ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
EDO
Query on EDO

Download Ideal Coordinates CCD File 
E [auth A]
F [auth A]
G [auth A]
L [auth B]
M [auth B]
E [auth A],
F [auth A],
G [auth A],
L [auth B],
M [auth B],
N [auth B],
S [auth C],
T [auth D]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
K
Query on K

Download Ideal Coordinates CCD File 
I [auth A],
J [auth A],
P [auth B],
Q [auth B]
POTASSIUM ION
K
NPYPAHLBTDXSSS-UHFFFAOYSA-N
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
ALY
Query on ALY
C, D
L-PEPTIDE LINKINGC8 H16 N2 O3LYS
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.84 Å
  • R-Value Free: 0.197 
  • R-Value Work: 0.164 
  • R-Value Observed: 0.166 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 82.048α = 90
b = 97.47β = 90
c = 104.254γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing

Structure Validation

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Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)United StatesGM49758

Revision History  (Full details and data files)

  • Version 1.0: 2020-12-16
    Type: Initial release
  • Version 1.1: 2020-12-30
    Changes: Database references
  • Version 1.2: 2023-10-18
    Changes: Data collection, Database references, Refinement description
  • Version 1.3: 2023-11-15
    Changes: Data collection, Derived calculations