4GM3

Crystal structure of human WD repeat domain 5 with compound MM-101


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.39 Å
  • R-Value Free: 0.226 
  • R-Value Work: 0.195 
  • R-Value Observed: 0.197 

wwPDB Validation   3D Report Full Report


This is version 2.0 of the entry. See complete history


Literature

High-affinity, small-molecule peptidomimetic inhibitors of MLL1/WDR5 protein-protein interaction.

Karatas, H.Townsend, E.C.Cao, F.Chen, Y.Bernard, D.Liu, L.Lei, M.Dou, Y.Wang, S.

(2013) J Am Chem Soc 135: 669-682

  • DOI: https://doi.org/10.1021/ja306028q
  • Primary Citation of Related Structures:  
    4GM3, 4GM8

  • PubMed Abstract: 

    Mixed lineage leukemia 1 (MLL1) is a histone H3 lysine 4 (H3K4) methyltransferase, and targeting the MLL1 enzymatic activity has been proposed as a novel therapeutic strategy for the treatment of acute leukemia harboring MLL1 fusion proteins. The MLL1/WDR5 protein-protein interaction is essential for MLL1 enzymatic activity. In the present study, we designed a large number of peptidomimetics to target the MLL1/WDR5 interaction based upon -CO-ARA-NH-, the minimum binding motif derived from MLL1. Our study led to the design of high-affinity peptidomimetics, which bind to WDR5 with K(i) < 1 nM and function as potent antagonists of MLL1 activity in a fully reconstituted in vitro H3K4 methyltransferase assay. Determination of co-crystal structures of two potent peptidomimetics in complex with WDR5 establishes their structural basis for high-affinity binding to WDR5. Evaluation of one such peptidomimetic, MM-102, in bone marrow cells transduced with MLL1-AF9 fusion construct shows that the compound effectively decreases the expression of HoxA9 and Meis-1, two critical MLL1 target genes in MLL1 fusion protein mediated leukemogenesis. MM-102 also specifically inhibits cell growth and induces apoptosis in leukemia cells harboring MLL1 fusion proteins. Our study provides the first proof-of-concept for the design of small-molecule inhibitors of the WDR5/MLL1 protein-protein interaction as a novel therapeutic approach for acute leukemia harboring MLL1 fusion proteins.


  • Organizational Affiliation

    Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
WD repeat-containing protein 5
A, B, C, D, E
A, B, C, D, E, F, G, H
313Homo 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

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
MM-101
I, J, K, L, M
I, J, K, L, M, N, O, P
5N/AMutation(s): 0 
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.39 Å
  • R-Value Free: 0.226 
  • R-Value Work: 0.195 
  • R-Value Observed: 0.197 
  • Space Group: P 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 48.943α = 90
b = 105.985β = 89.76
c = 120.907γ = 90.03
Software Package:
Software NamePurpose
HKL-2000data collection
PHASESphasing
PHENIXrefinement
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2013-07-31
    Type: Initial release
  • Version 1.1: 2023-09-13
    Changes: Data collection, Database references, Derived calculations, Refinement description
  • Version 2.0: 2023-11-15
    Changes: Atomic model, Data collection, Derived calculations