6DY7

WDR5 in complex with a WIN site inhibitor

  • Classification: TRANSFERASE/TRANSFERASE inhibitor
  • Organism(s): Homo sapiens
  • Expression System: Escherichia coli
  • Mutation(s): No 

  • Deposited: 2018-07-01 Released: 2019-03-13 
  • Deposition Author(s): Phan, J., Wang, F., Fesik, S.W.
  • Funding Organization(s): National Institutes of Health/National Cancer Institute (NIH/NCI), Department of Energy (DOE, United States), Michigan Economic Development Corporation and the Michigan Technology Tri-Corridor

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.199 
  • R-Value Work: 0.163 
  • R-Value Observed: 0.165 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Displacement of WDR5 from Chromatin by a WIN Site Inhibitor with Picomolar Affinity.

Aho, E.R.Wang, J.Gogliotti, R.D.Howard, G.C.Phan, J.Acharya, P.Macdonald, J.D.Cheng, K.Lorey, S.L.Lu, B.Wenzel, S.Foshage, A.M.Alvarado, J.Wang, F.Shaw, J.G.Zhao, B.Weissmiller, A.M.Thomas, L.R.Vakoc, C.R.Hall, M.D.Hiebert, S.W.Liu, Q.Stauffer, S.R.Fesik, S.W.Tansey, W.P.

(2019) Cell Rep 26: 2916-2928.e13

  • DOI: https://doi.org/10.1016/j.celrep.2019.02.047
  • Primary Citation of Related Structures:  
    6DY7, 6DYA, 6E1Y, 6E1Z, 6E22, 6E23

  • PubMed Abstract: 

    The chromatin-associated protein WDR5 is a promising target for pharmacological inhibition in cancer. Drug discovery efforts center on the blockade of the "WIN site" of WDR5, a well-defined pocket that is amenable to small molecule inhibition. Various cancer contexts have been proposed to be targets for WIN site inhibitors, but a lack of understanding of WDR5 target genes and of the primary effects of WIN site inhibitors hampers their utility. Here, by the discovery of potent WIN site inhibitors, we demonstrate that the WIN site links WDR5 to chromatin at a small cohort of loci, including a specific subset of ribosome protein genes. WIN site inhibitors rapidly displace WDR5 from chromatin and decrease the expression of associated genes, causing translational inhibition, nucleolar stress, and p53 induction. Our studies define a mode by which WDR5 engages chromatin and forecast that WIN site blockade could have utility against multiple cancer types.


  • Organizational Affiliation

    Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
WD repeat-containing protein 5304Homo 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
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
HH7 Binding MOAD:  6DY7 Kd: 6.62e+4 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.199 
  • R-Value Work: 0.163 
  • R-Value Observed: 0.165 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 81.162α = 90
b = 86.272β = 90
c = 40.594γ = 90
Software Package:
Software NamePurpose
SCALEPACKdata scaling
PHENIXrefinement
PDB_EXTRACTdata extraction
DENZOdata reduction
PHENIXphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Cancer Institute (NIH/NCI)United StatesHHSN261200800001E
National Institutes of Health/National Cancer Institute (NIH/NCI)United StatesCA68485
Department of Energy (DOE, United States)United StatesDE-AC02-06CH11357
Michigan Economic Development Corporation and the Michigan Technology Tri-CorridorUnited States085P1000817

Revision History  (Full details and data files)

  • Version 1.0: 2019-03-13
    Type: Initial release
  • Version 1.1: 2019-03-20
    Changes: Data collection, Database references
  • Version 1.2: 2019-11-06
    Changes: Author supporting evidence, Data collection
  • Version 1.3: 2019-12-04
    Changes: Author supporting evidence
  • Version 1.4: 2024-03-13
    Changes: Data collection, Database references