5M23

Modulation of MLL1 Methyltransferase Activity


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.97 Å
  • R-Value Free: 0.214 
  • R-Value Work: 0.166 
  • R-Value Observed: 0.169 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Controlled inhibition of methyltransferases using photoswitchable peptidomimetics: towards an epigenetic regulation of leukemia.

Albert, L.Xu, J.Wan, R.Srinivasan, V.Dou, Y.Vazquez, O.

(2017) Chem Sci 8: 4612-4618

  • DOI: https://doi.org/10.1039/c7sc00137a
  • Primary Citation of Related Structures:  
    5M23, 5M25

  • PubMed Abstract: 

    We describe a cell-permeable photoswitchable probe capable of modulating epigenetic cellular states by disruption of an essential protein-protein interaction within the MLL1 methyltransferase core complex. Our azobenzene-containing peptides selectively block the WDR5-MLL1 interaction by binding to WDR5 with high affinity ( K i = 1.25 nM). We determined the co-crystal structure of this photoswitchable peptiomimetic with WDR5 to understand the interaction at the atomic level. Importantly, the photoswitchable trans and cis conformers of the probe display a clear difference in their inhibition of MLL1. We further demonstrate that the designed photo-controllable azo-peptidomimetics affect the transcription of the MLL1-target gene Deptor, which regulates hematopoiesis and leukemogenesis, and inhibit the growth of leukemia cells. This strategy demonstrates the potential of photopharmacological inhibition of methyltransferase protein-protein interactions as a novel method for external epigenetic control, providing a new toolbox for controlling epigenetic states.


  • Organizational Affiliation

    Fachbereich Chemie , Philipps-Universität Marburg , Hans-Meerwein-Strasse 4 , 35043 Marburg , Germany . Email: olalla.vazquez@staff.uni-marburg.de.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
WD repeat-containing protein 5434Homo sapiensMutation(s): 0 
Gene Names: WDR5BIG3
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
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
7DC
Query on 7DC

Download Ideal Coordinates CCD File 
B [auth A]4-[(~{E})-[4-[[[(2~{S})-2-[[(2~{S})-2-[[(2~{S})-2-[[(2~{S})-2-azanyl-3-oxidanyl-propanoyl]amino]propanoyl]amino]-5-carbamimidamido-pentanoyl]amino]propanoyl]amino]methyl]phenyl]diazenyl]-~{N}-[(2~{S})-3-methyl-1-oxidanylidene-butan-2-yl]benzamide
C34 H49 N11 O7
ZYZPAXPFTDDNJW-KERJXBJTSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.97 Å
  • R-Value Free: 0.214 
  • R-Value Work: 0.166 
  • R-Value Observed: 0.169 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 80.553α = 90
b = 86.098β = 90
c = 40.407γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
SCALAdata scaling
PHENIXphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2017-06-28
    Type: Initial release
  • Version 1.1: 2017-10-11
    Changes: Database references
  • Version 1.2: 2024-01-17
    Changes: Data collection, Database references, Refinement description