8RD0

HUWE1 WWE domain in complex with compound 3


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.76 Å
  • R-Value Free: 
    0.215 (Depositor), 0.210 (DCC) 
  • R-Value Work: 
    0.197 (Depositor), 0.190 (DCC) 
  • R-Value Observed: 
    0.198 (Depositor) 

Starting Model: experimental
View more details

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted 51XClick on this verticalbar to view details

This is version 1.1 of the entry. See complete history


Literature

A ligand discovery toolbox for the WWE domain family of human E3 ligases.

Munzker, L.Kimani, S.W.Fowkes, M.M.Dong, A.Zheng, H.Li, Y.Dasovich, M.Zak, K.M.Leung, A.K.L.Elkins, J.M.Kessler, D.Arrowsmith, C.H.Halabelian, L.Bottcher, J.

(2024) Commun Biol 7: 901-901

  • DOI: https://doi.org/10.1038/s42003-024-06584-w
  • Primary Citation of Related Structures:  
    8R5N, 8R6A, 8R6B, 8R7O, 8RD0, 8RD1, 8RD7

  • PubMed Abstract: 

    The WWE domain is a relatively under-researched domain found in twelve human proteins and characterized by a conserved tryptophan-tryptophan-glutamate (WWE) sequence motif. Six of these WWE domain-containing proteins also contain domains with E3 ubiquitin ligase activity. The general recognition of poly-ADP-ribosylated substrates by WWE domains suggests a potential avenue for development of Proteolysis-Targeting Chimeras (PROTACs). Here, we present novel crystal structures of the HUWE1, TRIP12, and DTX1 WWE domains in complex with PAR building blocks and their analogs, thus enabling a comprehensive analysis of the PAR binding site structural diversity. Furthermore, we introduce a versatile toolbox of biophysical and biochemical assays for the discovery and characterization of novel WWE domain binders, including fluorescence polarization-based PAR binding and displacement assays, 15 N-NMR-based binding affinity assays and 19 F-NMR-based competition assays. Through these assays, we have characterized the binding of monomeric iso-ADP-ribose (iso-ADPr) and its nucleotide analogs with the aforementioned WWE proteins. Finally, we have utilized the assay toolbox to screen a small molecule fragment library leading to the successful discovery of novel ligands targeting the HUWE1 WWE domain.


  • Organizational Affiliation

    Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
E3 ubiquitin-protein ligase HUWE1
A, B, C, D
91Homo sapiensMutation(s): 0 
Gene Names: HUWE1
EC: 2.3.2.26
UniProt & NIH Common Fund Data Resources
Find proteins for Q7Z6Z7 (Homo sapiens)
Explore Q7Z6Z7 
Go to UniProtKB:  Q7Z6Z7
PHAROS:  Q7Z6Z7
GTEx:  ENSG00000086758 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ7Z6Z7
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
51X (Subject of Investigation/LOI)
Query on 51X

Download Ideal Coordinates CCD File 
I [auth C],
L [auth D]
(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetic acid
C10 H7 N O4
WQINSVOOIJDOLJ-UHFFFAOYSA-N
CL
Query on CL

Download Ideal Coordinates CCD File 
E [auth A]
F [auth B]
G [auth B]
H [auth C]
J [auth D]
CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.76 Å
  • R-Value Free:  0.215 (Depositor), 0.210 (DCC) 
  • R-Value Work:  0.197 (Depositor), 0.190 (DCC) 
  • R-Value Observed: 0.198 (Depositor) 
Space Group: P 43 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 62.795α = 90
b = 62.795β = 90
c = 231.755γ = 90
Software Package:
Software NamePurpose
XDSdata reduction
autoPROCdata scaling
STARANISOdata scaling
BUSTERrefinement
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted 51XClick on this verticalbar to view details

Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
European Union (EU)European Union875510

Revision History  (Full details and data files)

  • Version 1.0: 2024-07-31
    Type: Initial release
  • Version 1.1: 2024-08-07
    Changes: Database references