6PG8

WDR5delta23 bound to (2-(3-phenylpropyl)-1H-imidazol-4-yl)methanol


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.67 Å
  • R-Value Free: 0.207 
  • R-Value Work: 0.187 
  • R-Value Observed: 0.188 

wwPDB Validation   3D Report Full Report

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This is version 1.1 of the entry. See complete history


Literature

Fragment screening for a protein-protein interaction inhibitor to WDR5.

Dennis, M.L.Morrow, B.J.Dolezal, O.Cuzzupe, A.N.Stupple, A.E.Newman, J.Bentley, J.Hattarki, M.Nuttall, S.D.Foitzik, R.C.Street, I.P.Stupple, P.A.Monahan, B.J.Peat, T.S.

(2019) Struct Dyn 6: 064701-064701

  • DOI: https://doi.org/10.1063/1.5122849
  • Primary Citation of Related Structures:  
    6PG3, 6PG4, 6PG5, 6PG6, 6PG7, 6PG8, 6PG9, 6PGA, 6PGB, 6PGC, 6PGD, 6PGE, 6PGF

  • PubMed Abstract: 

    The WD40-repeat protein WDR5 scaffolds various epigenetic writers and is a critical component of the mammalian SET/MLL histone methyltransferase complex. Dysregulation of the MLL1 catalytic function is associated with mixed-lineage leukemia, and antagonism of the WDR5-MLL1 interaction by small molecules has been proposed as a therapeutic strategy for MLL-rearranged cancers. Small molecule binders of the "WIN" site of WDR5 that cause displacement from chromatin have been additionally implicated to be of broader use in cancer treatment. In this study, a fragment screen with Surface Plasmon Resonance (SPR) was used to identify a highly ligand-efficient imidazole-containing compound that is bound in the WIN site. The subsequent medicinal chemistry campaign-guided by a suite of high-resolution cocrystal structures with WDR5-progressed the initial hit to a low micromolar binder. One outcome from this study is a moiety that substitutes well for the side chain of arginine; a tripeptide containing one such substitution was resolved in a high resolution structure (1.5 Å) with a binding mode analogous to the native tripeptide. SPR furthermore indicates a similar residence time ( k d = ∼0.06 s -1 ) for these two analogs. This novel scaffold therefore represents a possible means to overcome the potential permeability issues of WDR5 ligands that possess highly basic groups like guanidine. The series reported here furthers the understanding of the WDR5 WIN site and functions as a starting point for the development of more potent WDR5 inhibitors that may serve as cancer therapeutics.


  • Organizational Affiliation

    Commonwealth Scientific and Industrial Research Organisation (CSIRO), Biomedical Program, Parkville, Victoria 3052, Australia.


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
314Homo 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
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
OGY (Subject of Investigation/LOI)
Query on OGY

Download Ideal Coordinates CCD File 
E [auth A],
G [auth B],
I [auth C],
K [auth D]
[2-(3-phenylpropyl)-1H-imidazol-4-yl]methanol
C13 H16 N2 O
YJBVUMXRLPWRCM-UHFFFAOYSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
H [auth B]SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
CL
Query on CL

Download Ideal Coordinates CCD File 
F [auth A],
J [auth C],
L [auth D],
M [auth D]
CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Binding Affinity Annotations 
IDSourceBinding Affinity
OGY Binding MOAD:  6PG8 Kd: 1.40e+5 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.67 Å
  • R-Value Free: 0.207 
  • R-Value Work: 0.187 
  • R-Value Observed: 0.188 
  • Space Group: P 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 54.118α = 104.7
b = 75.831β = 96.41
c = 79.239γ = 105.23
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing

Structure Validation

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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2019-12-11
    Type: Initial release
  • Version 1.1: 2023-10-11
    Changes: Data collection, Database references, Refinement description