6TV4

CFF-Notum complex


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.53 Å
  • R-Value Free: 0.214 
  • R-Value Work: 0.170 
  • R-Value Observed: 0.172 

Starting Model: experimental
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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 CFFClick on this verticalbar to view details

This is version 1.2 of the entry. See complete history


Literature

Caffeine inhibits Notum activity by binding at the catalytic pocket.

Zhao, Y.Ren, J.Hillier, J.Lu, W.Jones, E.Y.

(2020) Commun Biol 3: 555-555

  • DOI: https://doi.org/10.1038/s42003-020-01286-5
  • Primary Citation of Related Structures:  
    6TUZ, 6TV4

  • PubMed Abstract: 

    Notum inhibits Wnt signalling via enzymatic delipidation of Wnt ligands. Restoration of Wnt signalling by small molecule inhibition of Notum may be of therapeutic benefit in a number of pathologies including Alzheimer's disease. Here we report Notum activity can be inhibited by caffeine (IC 50 19 µM), but not by demethylated caffeine metabolites: paraxanthine, theobromine and theophylline. Cellular luciferase assays show Notum-suppressed Wnt3a function can be restored by caffeine with an EC 50 of 46 µM. The dissociation constant (K d ) between Notum and caffeine is 85 µM as measured by surface plasmon resonance. High-resolution crystal structures of Notum complexes with caffeine and its minor metabolite theophylline show both compounds bind at the centre of the enzymatic pocket, overlapping the position of the natural substrate palmitoleic lipid, but using different binding modes. The structural information reported here may be of relevance for the design of more potent brain-accessible Notum inhibitors.


  • Organizational Affiliation

    Division of Structural Biology, Wellcome Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK. yuguang@strubi.ox.ac.uk.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Palmitoleoyl-protein carboxylesterase NOTUM383Homo sapiensMutation(s): 1 
Gene Names: NOTUMOK/SW-CL.30
EC: 3.1.1.98
UniProt & NIH Common Fund Data Resources
Find proteins for Q6P988 (Homo sapiens)
Explore Q6P988 
Go to UniProtKB:  Q6P988
PHAROS:  Q6P988
GTEx:  ENSG00000185269 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ6P988
Glycosylation
Glycosylation Sites: 1Go to GlyGen: Q6P988-1
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 5 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
NAG
Query on NAG

Download Ideal Coordinates CCD File 
F [auth A]2-acetamido-2-deoxy-beta-D-glucopyranose
C8 H15 N O6
OVRNDRQMDRJTHS-FMDGEEDCSA-N
CFF (Subject of Investigation/LOI)
Query on CFF

Download Ideal Coordinates CCD File 
Q [auth A]CAFFEINE
C8 H10 N4 O2
RYYVLZVUVIJVGH-UHFFFAOYSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
B [auth A]
C [auth A]
D [auth A]
E [auth A]
I [auth A]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
GOL
Query on GOL

Download Ideal Coordinates CCD File 
R [auth A],
S [auth A],
T [auth A],
U [auth A],
V [auth A]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
DMS
Query on DMS

Download Ideal Coordinates CCD File 
G [auth A],
H [auth A]
DIMETHYL SULFOXIDE
C2 H6 O S
IAZDPXIOMUYVGZ-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.53 Å
  • R-Value Free: 0.214 
  • R-Value Work: 0.170 
  • R-Value Observed: 0.172 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 59.987α = 90
b = 71.574β = 90
c = 78.313γ = 90
Software Package:
Software NamePurpose
xia2data scaling
REFMACrefinement
PDB_EXTRACTdata extraction
xia2data reduction
MOLREPphasing

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 CFFClick on this verticalbar to view details

Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Medical Research Council (MRC, United Kingdom)United KingdomMR/M000141/1
Cancer Research UKUnited KingdomC375/A17721

Revision History  (Full details and data files)

  • Version 1.0: 2020-10-28
    Type: Initial release
  • Version 1.1: 2024-01-24
    Changes: Data collection, Database references, Refinement description
  • Version 1.2: 2024-11-20
    Changes: Structure summary