RCSB PDB - 6WYP: Crystal structure of Danio rerio histone deacetylase 6 catalytic domain 1 (CD1) K330L mutant complexed with SAHA-BPyne

 6WYP

Crystal structure of Danio rerio histone deacetylase 6 catalytic domain 1 (CD1) K330L mutant complexed with SAHA-BPyne


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free: 0.243 
  • R-Value Work: 0.203 
  • R-Value Observed: 0.205 

Starting Model: experimental
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Ligand Structure Quality Assessment 

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This is version 1.2 of the entry. See complete history


Literature

Binding of inhibitors to active-site mutants of CD1, the enigmatic catalytic domain of histone deacetylase 6.

Osko, J.D.Christianson, D.W.

(2020) Acta Crystallogr F Struct Biol Commun 76: 428-437

  • DOI: https://doi.org/10.1107/S2053230X20010250
  • Primary Citation of Related Structures:  
    6WYO, 6WYP, 6WYQ

  • PubMed Abstract: 

    The zinc hydrolase histone deacetylase 6 (HDAC6) is unique among vertebrate deacetylases in that it contains two catalytic domains, designated CD1 and CD2. Both domains are fully functional as lysine deacetylases in vitro. However, the in vivo function of only the CD2 domain is well defined, whereas that of the CD1 domain is more enigmatic. Three X-ray crystal structures of HDAC6 CD1-inhibitor complexes are now reported to broaden the understanding of affinity determinants in the active site. Notably, cocrystallization with inhibitors was facilitated by using active-site mutants of zebrafish HDAC6 CD1. The first mutant studied, H82F/F202Y HDAC6 CD1, was designed to mimic the active site of human HDAC6 CD1. The structure of its complex with trichostatin A was generally identical to that with the wild-type zebrafish enzyme. The second mutant studied, K330L HDAC6 CD1, was prepared to mimic the active site of HDAC6 CD2. It has previously been demonstrated that this substitution does not perturb inhibitor binding conformations in HDAC6 CD1; here, this mutant facilitated cocrystallization with derivatives of the cancer chemotherapy drug suberoylanilide hydroxamic acid (SAHA). These crystal structures allow the mapping of inhibitor-binding regions in the outer active-site cleft, where one HDAC isozyme typically differs from another. It is expected that these structures will help to guide the structure-based design of inhibitors with selectivity against HDAC6 CD1, which in turn will enable new chemical biology approaches to probe its cellular function.


  • Organizational Affiliation

    Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philaldelphia, PA 19104-6323, USA.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Histone deacetylase 6380Danio rerioMutation(s): 1 
Gene Names: hdac6
UniProt
Find proteins for F8W4B7 (Danio rerio)
Explore F8W4B7 
Go to UniProtKB:  F8W4B7
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupF8W4B7
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free: 0.243 
  • R-Value Work: 0.203 
  • R-Value Observed: 0.205 
  • Space Group: C 2 2 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 66.029α = 90
b = 95.17β = 90
c = 119.71γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
iMOSFLMdata reduction
Aimlessdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted UFSClick on this verticalbar to view details

Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Human Genome Research Institute (NIH/NHGRI)United StatesGM49758

Revision History  (Full details and data files)

  • Version 1.0: 2020-09-02
    Type: Initial release
  • Version 1.1: 2020-09-16
    Changes: Database references
  • Version 1.2: 2023-10-18
    Changes: Data collection, Database references, Refinement description