4ERY

X-ray structure of WDR5-MLL3 Win motif peptide binary complex


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.30 Å
  • R-Value Free: 0.209 
  • R-Value Work: 0.187 
  • R-Value Observed: 0.188 

wwPDB Validation   3D Report Full Report


This is version 1.3 of the entry. See complete history


Literature

Structural basis for WDR5 interaction (Win) motif recognition in human SET1 family histone methyltransferases.

Dharmarajan, V.Lee, J.H.Patel, A.Skalnik, D.G.Cosgrove, M.S.

(2012) J Biol Chem 287: 27275-27289

  • DOI: https://doi.org/10.1074/jbc.M112.364125
  • Primary Citation of Related Structures:  
    4ERQ, 4ERY, 4ERZ, 4ES0, 4ESG, 4EWR

  • PubMed Abstract: 

    Translocations and amplifications of the mixed lineage leukemia-1 (MLL1) gene are associated with aggressive myeloid and lymphocytic leukemias in humans. MLL1 is a member of the SET1 family of histone H3 lysine 4 (H3K4) methyltransferases, which are required for transcription of genes involved in hematopoiesis and development. MLL1 associates with a subcomplex containing WDR5, RbBP5, Ash2L, and DPY-30 (WRAD), which together form the MLL1 core complex that is required for sequential mono- and dimethylation of H3K4. We previously demonstrated that WDR5 binds the conserved WDR5 interaction (Win) motif of MLL1 in vitro, an interaction that is required for the H3K4 dimethylation activity of the MLL1 core complex. In this investigation, we demonstrate that arginine 3765 of the MLL1 Win motif is required to co-immunoprecipitate WRAD from mammalian cells, suggesting that the WDR5-Win motif interaction is important for the assembly of the MLL1 core complex in vivo. We also demonstrate that peptides that mimic SET1 family Win motif sequences inhibit H3K4 dimethylation by the MLL1 core complex with varying degrees of efficiency. To understand the structural basis for these differences, we determined structures of WDR5 bound to six different naturally occurring Win motif sequences at resolutions ranging from 1.9 to 1.2 Å. Our results reveal that binding energy differences result from interactions between non-conserved residues C-terminal to the Win motif and to a lesser extent from subtle variation of residues within the Win motif. These results highlight a new class of methylation inhibitors that may be useful for the treatment of MLL1-related malignancies.


  • Organizational Affiliation

    Department of Biology, Syracuse University, Syracuse, New York 13244, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
WD repeat-containing protein 5312Homo sapiensMutation(s): 0 
Gene Names: BIG3WDR5
UniProt & NIH Common Fund Data Resources
Find proteins for P61964 (Homo sapiens)
Explore P61964 
Go to UniProtKB:  P61964
PHAROS:  P61964
GTEx:  ENSG00000196363 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP61964
Sequence Annotations
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  • Reference Sequence

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Histone-lysine N-methyltransferase MLL3B [auth D]14Homo sapiensMutation(s): 0 
EC: 2.1.1.43
UniProt & NIH Common Fund Data Resources
Find proteins for Q8NEZ4 (Homo sapiens)
Explore Q8NEZ4 
Go to UniProtKB:  Q8NEZ4
PHAROS:  Q8NEZ4
GTEx:  ENSG00000055609 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ8NEZ4
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.30 Å
  • R-Value Free: 0.209 
  • R-Value Work: 0.187 
  • R-Value Observed: 0.188 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 46.53α = 90
b = 68.25β = 90
c = 87.88γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
MOLREPphasing
PHENIXrefinement
PDB_EXTRACTdata extraction

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2012-05-16
    Type: Initial release
  • Version 1.1: 2015-02-11
    Changes: Database references
  • Version 1.2: 2017-11-15
    Changes: Refinement description
  • Version 1.3: 2024-02-28
    Changes: Data collection, Database references