7B4X

Notum complex with ARUK3002697


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.24 Å
  • R-Value Free: 0.219 
  • R-Value Work: 0.202 
  • R-Value Observed: 0.203 

Starting Model: experimental
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wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Structural Analysis and Development of Notum Fragment Screening Hits.

Zhao, Y.Mahy, W.Willis, N.J.Woodward, H.L.Steadman, D.Bayle, E.D.Atkinson, B.N.Sipthorp, J.Vecchia, L.Ruza, R.R.Harlos, K.Jeganathan, F.Constantinou, S.Costa, A.Kjaer, S.Bictash, M.Salinas, P.C.Whiting, P.Vincent, J.P.Fish, P.V.Jones, E.Y.

(2022) ACS Chem Neurosci 13: 2060-2077

  • DOI: https://doi.org/10.1021/acschemneuro.2c00325
  • Primary Citation of Related Structures:  
    7B4X, 7B84, 7B86, 7B87, 7B89, 7B8C, 7B8D, 7B8F, 7B8G, 7B8J, 7B8K, 7B8L, 7B8M, 7B8N, 7B8O, 7B8U, 7B8X, 7B8Y, 7B8Z, 7B98, 7B99, 7B9D, 7B9I, 7B9N, 7B9U, 7BA1, 7BAC, 7BAP, 7BC8, 7BC9, 7BCC, 7BCD, 7BCF, 7BCH, 7BCI, 7BCK, 7BCL, 7BD2, 7BD3, 7BD4, 7BD5, 7BD6, 7BD8, 7BD9, 7BDA, 7BDB, 7BDC, 7BDD, 7BDF, 7BDG

  • PubMed Abstract: 

    The Wnt signaling suppressor Notum is a promising target for osteoporosis, Alzheimer's disease, and colorectal cancers. To develop novel Notum inhibitors, we used an X-ray crystallographic fragment screen with the Diamond-SGC Poised Library (DSPL) and identified 59 fragment hits from the analysis of 768 data sets. Fifty-eight of the hits were found bound at the enzyme catalytic pocket with potencies ranging from 0.5 to >1000 μM. Analysis of the fragments' diverse binding modes, enzymatic inhibitory activities, and chemical properties led to the selection of six hits for optimization, and five of these resulted in improved Notum inhibitory potencies. One hit, 1 - phenyl-1,2,3-triazole 7 , and its related cluster members, have shown promising lead-like properties. These became the focus of our fragment development activities, resulting in compound 7d with IC 50 0.0067 μM. The large number of Notum fragment structures and their initial optimization provided an important basis for further Notum inhibitor development.


  • Organizational Affiliation

    Division of Structural Biology, Wellcome Centre for Human Genetics, University of Oxford, The Henry Wellcome Building for Genomic Medicine, Roosevelt Drive, Oxford OX3 7BN, U.K.


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
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
SWT (Subject of Investigation/LOI)
Query on SWT

Download Ideal Coordinates CCD File 
M [auth A]6-(4-methylphenyl)sulfanyl-2~{H}-[1,2,4]triazolo[4,3-b]pyridazin-3-one
C12 H10 N4 O S
SVJSYMYGSKESLF-UHFFFAOYSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
B [auth A]
C [auth A]
D [auth A]
E [auth A]
F [auth A]
B [auth A],
C [auth A],
D [auth A],
E [auth A],
F [auth A],
O [auth A],
P [auth A]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
DMS
Query on DMS

Download Ideal Coordinates CCD File 
G [auth A],
H [auth A],
I [auth A]
DIMETHYL SULFOXIDE
C2 H6 O S
IAZDPXIOMUYVGZ-UHFFFAOYSA-N
EDO
Query on EDO

Download Ideal Coordinates CCD File 
J [auth A],
K [auth A],
L [auth A],
N [auth A]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
SWT BindingDB:  7B4X IC50: 27 (nM) from 1 assay(s)
EC50: 86 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.24 Å
  • R-Value Free: 0.219 
  • R-Value Work: 0.202 
  • R-Value Observed: 0.203 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 59.193α = 90
b = 72.995β = 90
c = 77.73γ = 90
Software Package:
Software NamePurpose
xia2data scaling
PHENIXrefinement
PDB_EXTRACTdata extraction
xia2data reduction
MOLREPphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2022-01-12
    Type: Initial release
  • Version 1.1: 2022-07-27
    Changes: Database references
  • Version 1.2: 2024-01-31
    Changes: Data collection, Refinement description